Ingestion Of Tramadol Research Articles

Exposure to immediate-release tramadol in children 6 years and under – a nationwide French poison control center study

Introduction Data regarding immediate-release (IR)-tramadol exposures in children remain sparse. We aimed to investigate the incidence of IR-tramadol exposures in ≤6-year-old children, to describe the characteristics and resulting outcome of ingestions involving IR-tramadol alone, and to estimate a clinically relevant toxic dose in this population. Methods Retrospective analysis of IR-tramadol exposures in ≤6-year-old children, collected by the French Poison Control Centers (PCCs) in 2003–2019. The incidence was estimated using IR-tramadol prescription data from the Health Improvement Network database (the French version of THIN). The Poison severity score (PSS) was used to grade severity. Results We found 1260 IR-tramadol exposures in ≤6-year-old children. The number of cases per 100,000 IR-tramadol-treated patients increased over time (p < .0001). One hundred forty-five cases involving IR-tramadol alone were analyzed. The median age was 3.0 years (IQR: 1.9, 4.0), the M/F ratio was 1.5 and the median dose was 5.0 mg/kg (IQR 3.3–11.1). Half of the children (49.7%) remained asymptomatic (PSS0) while 29.6% and 14.5% developed minor (PSS1) or moderate-to-severe (PSS2–PSS3) neurological symptoms, respectively. Twelve children developed respiratory depression. No seizures and no fatality were reported. All symptomatic children recovered within 24 h. The ingested IR-tramadol dose was positively correlated with the PSS (p < .0001). Using a receiver operating characteristic (ROC) curve approach (area under the curve, 0.92; p < .001), ingestion of ≥7.4 mg/kg IR-tramadol was appropriate to recommend hospital referral (sensitivity, 100% [95% confidence interval (CI), 85–100]; specificity, 73% [95% CI, 64–80]; predictive positive value, 39% [95% CI, 35–57]; negative predictive value, 100% [95% CI, 96–100]). Children who ingested <7.4 mg/kg IR-tramadol developed no (n = 68) or minor (n = 22) neurological symptoms. Conclusions Despite increasing tramadol prescriptions in adults during the study period in France, oral exposure to IR-tramadol in ≤6-year-old children was rare but possibly responsible for severe toxicity. Children with no underlying disease and concomitant medication ingesting <7.4 mg/kg IR-tramadol alone could be observed at home. However, given the observed variability in the onset of seizures after tramadol ingestion, which can occur at ingested tramadol doses below 7.4 mg and even at therapeutic doses, parents or guardians should be specifically warned about the risk of seizures.

Acute Tramadol Ingestion With Transient Acute Kidney Injury in an Adolescent Female.

Renal toxicity has been described with tramadol overdoses; however, it is typically associated with rhabdomyolysis, multiorgan failure and/or mortality. Our patient was a 16-year-old female who was evaluated following an intentional tramadol ingestion, estimated 27.8 to 37 mg/kg, and had a seizure prior to arriving at our health care facility. Her symptoms were consistent with a tramadol ingestion; however, she developed transient acute renal impairment (peak serum creatinine, 4.04 mg/dL), which improved over 6 days with minimal intervention. No other causes were identified to explain her acute renal impairment thus it was attributed to the tramadol overdose. Providers should be aware that transient acute renal impairment could occur with an intentional tramadol ingestion and may not require aggressive intervention.

Effects of Separate and Combined Chronic Ingestion of Tramadol and Codeine on Aggressive Behaviour among Female Albino Rats

The relationship between drug use and aggressive behaviour and its consequences on social and financial burden on society is a source of recent concern. This study, therefore, examined the effects of acute exposure to Codeine and Tramadol on aggressive behaviour. Twenty-Eight (28) participants (Female Albino Rats) weighing between 120-150g and 4-6 weeks old, collected from the University of Ibadan Veterinary animal farm were used for this study. They were divided into 5 experimental groups of Codeine, Tramadol, combined Codeine and Tramadol, Control and intruder groups with 6 rats in each group except the intruder group with 4 rats. They were exposed to, 8mg/kg of codeine for the codeine group, 20mg/kg of tramadol for the tramadol group, combined 8mg/kg of codeine and 20mg/kg of tramadol for the combined group, normal saline for the control group and no treatment for the intruder group for 28 days. The rats were observed daily after treatment for, biting, dominant posture and scratching as attributes of aggressive behaviour. Randomized block ANOVA showed a significant effect of Codeine and Tramadol on aggressive behaviour among female albino rats, F (3,2010) = 53.53, p &lt; 0.001, η2= .07. Female albino rats in the tramadol treatment group significantly exhibited more aggression (x ̅= 14.08) than control group (x ̅=11.53) codeine group (x ̅=11.41) and combined group (x ̅=7.36). The mean differences were significant (p&lt;.001). It was concluded that chronic exposure to tramadol has implications for aggressive tendencies and combined exposure to tramadol and codeine may be injurious to health.

Pediatric Toxicoepidemiology of Tramadol Intoxication in Iran: A 5-year Cross-Sectional Study.

Objective:We aimed to find the toxicoepidemiological indicators of tramadol poisoning in children and also the relationship of these indicators (such as demographic characteristics, and referral time) with the final therapeutic outcome.Methods:In this cross-sectional study with retrospective data collection, we included the records for all the patients under 18 that have been admitted due to tramadol poisoning between 2010 and 2015 to Noor and Ali-Asghar (PBUH) University hospital which serves as the referral medical center for acute poisonings management in the central part of Iran and is located in Isfahan. Demographic characteristics, ingested dose, dosage forms, clinical manifestations, coingested drugs, and the outcome of treatment for all pediatric patients were documented and descriptively analyzed.Findings:Demographic and clinical data of a total of 189 patients including 101 male (53.4%) with a mean age of 16.66 ± 2.64 years were abstracted and included in this study. The average time between tramadol ingestion and hospital admission was 3.39 ± 3.23 h. Mean duration of hospitalization was 12.3 ± 10.7 h. In all cases, the route of drug exposure was oral, and the most common form of drug dosage form was 100 mg tablets (n = 122) proceeded by 200 mg tablets (n = 32). The mean estimated dose of ingested tramadol was 1126 ± 1061 mg (median, 900 range, 50–7000 mg). 43.9% of the poisoned patients were high school students, and 23.3% had a high school diploma. Intentional intoxications were reported in 93.1% cases and 42.9% had coingestions. Activated charcoal (87.3%), gastric lavage (59.3%), oxygen therapy with mask (46.6%), naloxone (11.6%), anticonvulsants (13.2%), and intubation and ventilation (5.3%) were done as first-line therapeutic measures.Conclusion:Our results suggest that the trend of acute tramadol poisoning among children is decreasing, mostly accidental in adolescents and commonly intentional among young children. Proper education to improve emotional intelligence for young adults and to keep drugs out of reach of the children and safer packaging is recommended to reduce tramadol poisoning incidence in the pediatric population.

Tramadol Does Not Improve Performance or Impair Motor Function in Trained Cyclists.

To investigate the hypothesis that a therapeutic oral dose of Tramadol improves cycling time trial performance and compromises motor-cognitive performance in highly trained cyclists. Following two familiarization trials, 16 highly trained cyclists completed a preloaded time trial (1 h at 60% of peak power followed by a 15-km time trial) after ingestion of 100 mg Tramadol or placebo in a double-blind placebo-controlled counterbalanced crossover design separated by at least 4 d washout. Visuomotor tracking and math tasks were completed during the preload (n = 10) to evaluate effects on cognition and fine motor performance. Time trial mean power output (298 ± 42 W vs 294 ± 44 W) and performance (1474 ± 77 s vs 1483 ± 85 s) were similar with Tramadol and placebo treatment, respectively. In addition, there were no differences in perceived exertion, reported pain, blood pH, lactate, or bicarbonate concentrations across trials. Heart rate was higher (P < 0.001) during the Tramadol time trial (171 ± 8 bpm) compared with placebo (167 ± 9 bpm). None of the combined motor-cognitive tasks were impaired by Tramadol ingestion, in fact fine motor performance was slightly improved (P < 0.05) in the Tramadol trial compared with placebo. In highly trained cyclists, ingestion of 100 mg Tramadol does not improve performance in a 15-km cycling time trial that was completed after a 1-h preload at 60% peak power. Additionally, a therapeutic dose of Tramadol does not compromise complex motor-cognitive or simple fine motor performances.

Accidental tramadol ingestion in children admitted in tertiary care centre

Background: Tramadol use has been increasing in the adult and pediatric population. Practitioners must be alert because Tramadol misuse can lead to severe intoxication in which respiratory failure and seizures are frequent. Overdoses can lead to death. We report 47 pediatric cases with history of accidental tramadol exposure in children.Methods: An observational, retrospective, single center case -series of children with a history of accidental tramadol exposure in children admitted in pediatric intensive care unit of tertiary care center, Niloufer Hospital (Osmania Medical College) Hyderabad, Telangana India.Results: Of 47 children, 22 (47%) are male and 25 (53%) were female. At presentation 11 (23%) had loss of consciousness, 14 (29%) seizures, 17 (36%) hypotonia was noted. Pupils were miotic in 22 (47%) mydriatic in 2 (4.2%) normal in rest of children. Hemodynamic instability noted in 13 (27.6%). Serotonin syndrome (tachycardia, hyperthermia, hypertension, hyper reflex, clonus) was noted on 5 (10.6%) children. Respiratory depression was seen in 4 (8%) children who needed ventilatory support. Antidote Naloxone was given in 7 children. No adverse reaction was noted with Naloxone. All 47 children were successfully discharged.Conclusions: Overdoses can lead to death and practitioners must be alert because of the increasing use of tramadol in the adult and pediatric population. The handling of the tramadol should be explained to parents and general population and naloxone could be efficient when opioid toxicity signs are present.

Characterizing the Toxicity and Dose-Effect Profile of Tramadol Ingestions in Children.

Tramadol can cause life-threatening toxicity in overdose; however, data on its toxicity in children are lacking. This study investigates toxicity associated with tramadol ingestions in children. The hypothesis is that children will experience dose-related central nervous system and respiratory depression and seizures. A retrospective evaluation of cases from the National Poison Center Data System between January 1, 2000, and December 31, 2013, was performed. Inclusion criteria were age below 6 years and single-substance acute tramadol ingestion. For dose-effect analysis, cases with sufficient dose quantity information were included. There were 7334 cases that met inclusion criteria. Outcomes were 84.8% no effect, 12.6% minor, 2.2% moderate, and 0.4% major effect. There was 1 fatality. Most of the children (36.4%) were treated/released from the emergency department; other management sites were home (36.4%), admission (5.9%), and others (3.2%). In the 1115 children with symptoms, drowsiness (N = 611) and vomiting (N = 178) occurred most frequently. More serious clinical effects included respiratory depression in 36 and seizures in 24 children. Of 2772 children with milligram dose recorded, there were 10 cases of respiratory depression and 6 of seizure. Median doses for respiratory depression and seizure were 225 (range, 50-600 mg) and 525 mg (range, 50-1050 mg), respectively. The minimum weight-based dose for respiratory depression/arrest was 7.9 mg/kg and for seizures, 4.8 mg/kg. Seizure and respiratory depression are uncommon in pediatric tramadol ingestions. Given the small number of patients with dose data and lack of laboratory confirmation of dose, more studies are needed to determine the minimum dose at which medical management is recommended.

Seizures in tramadol overdoses reported in the ToxIC registry: predisposing factors and the role of naloxone

Importance: Tramadol prescriptions have increased as fewer schedule II and III drugs are prescribed. There has been a concomitant increase in overdoses and adverse events recorded in the National Poison Data System. Seizure activity after tramadol overdose or therapeutic use is a well-documented adverse event. The primary objective is to evaluate the characteristics associated with seizures following single agent tramadol ingestion. Secondarily we aim to compare the rate of seizures in individuals treated, and not treated, with naloxone.Methods: We searched the Toxicology Investigators Consortium data registry for all cases of single agent tramadol ingestions from 01/01/2014 through 12/31/2017. Descriptive statistics were used to evaluate characteristics associated with increased risk of seizures. Binary logistic regressions were used to evaluate the associations between seizures and age, race, acuity, intent, toxidromes, symptoms, and treatments.Results: There were 80 single ingestion tramadol cases entered into the registry. Seizures developed in 42 (52.5%) patients. Asian patients (OR = 7.2, 95% CI: 1.9–27.3, p = .004) and patients abusing or misusing tramadol (OR = 3.2, 95% CI: 1.2–8.3, p = .02) more likely to develop seizures. Patients exhibiting an opioid toxidrome were significantly less likely to develop seizures (OR = 0.12, 95% CI: 0.03–0.60). Ingestion of tramadol as a means of self-harm and age were not associated with an increased risk of seizures. There was no significant association between naloxone administration and seizures (OR = 0.30, 95% CI 0.07–1.25).Conclusions: Based on data from the ToxIC registry, tramadol induced seizures are more likely in Asian patients and those abusing or misusing the medication. There was no association found between the development of seizures and the use of naloxone.

Occurrence and Recurrence of Seizures and Related Factors in Patients With Tramadol Ingestion

Background: Rate of tramadol poisoning and seizure and its complications is high in Iran. We investigated the occurrence and recurrence of tramadol-induced seizures and related factors in patients with tramadol poisoning.Methods: This was a descriptive longitudinal study conducted in a poisoning referral hospital in Tehran, Iran. During April to June 2017, adult patients (≥16 years) with tramadol ingestion and poisoning admitted to hospital were selected by convenience sampling method. We studied the rate of seizure occurrence and recurrence among them. Also, the association between seizure occurrence and recurrence and patients’ demographic characteristics and poisoning-related factors were investigated. Data were analyzed by SPSS 16 and significant level was set at <0.05.Results: In total, 250 patients participated in the study. Their mean age was 26.39 years and 214 (85.6%) of them were male. Of all, 159 (63.6%) were single, 106 (42.4%) were unemployed and 24 (9.6%) were students. Main reason of tramadol consumption was suicide. Co-administration of drugs was reported in 83 (33.2%) cases. Incidence of seizure occurrence and recurrence were 31% and 38.5%, respectively. There was no statistically significant relationship between the occurrence and recurrence of seizures and patients’ age, gender, marital status, occupation, reason for tramadol consumption, co-administration of drugs and naloxone administration. Probability of seizure occurrence and recurrence raised with increased tramadol dose (P<0.001 and P<0.01, respectively). Seizure recurrence led to longer hospital stay (P<0.001).Conclusion: Rate of the occurrence and recurrence of tramadol-induced seizure seems clinically significant, but the prognosis is generally good in cases with seizure. Greater ingested dose and late hospital admission were associated with higher probability of seizure occurrence and recurrence. Further studies are required to investigate the risk factors of tramadol-induced seizure.

Correlation between plasma concentrations of tramadol and its metabolites and the incidence of seizure in tramadol-intoxicated patients.

Seizure is one of the important symptoms of tramadol poisoning, but its causes are still unknown. The aim of this study is to find a relationship between tramadol and the concentrations of its metabolites versus the incidence of seizures following the consumption of high doses of tramadol. For this purpose, the blood samples of 120 tramadol-intoxicated patients were collected. The patients were divided in two groups (seizure and non-seizure). The concentrations of tramadol and its metabolites (M1, M2 and M5) were measured by using a high-performance liquid chromatography method. The relationship between tramadol and the levels of its metabolites and seizure incidences was also investigated. In 72% of the patients, seizures occurred in the first 3 h after the ingestion of tramadol. The seizure incidences were significantly correlated with the patients' gender, concentrations of tramadol, M1 and M2 and the history of previous seizures (p<0.001). The average concentration of M2 was significantly higher in males (p=0.003). A previous history of the use of sedative-hypnotics and the co-ingestion of benzodiazepines and other opioids were shown to significantly decrease the rate of seizure. The rate of seizure was directly related to the concentrations of tramadol and its metabolites. Higher M2 concentration in males can be considered a reason for increased incidences of seizures in males. The plasma concentration of M1 affected the onset of seizure. Therefore, it can be concluded that differences in the levels of the metabolites can affect the threshold of seizure in tramadol-intoxicated patients.

Respiratory Apnea in Patients with Acute Poisoning by Tramadol (Two Years Study)

Background: Tramadol is an analgesic drug being abused today a lot. Excessive ingestion will lead to hazardous complications such as convulsion and occasionally respiratory apnea. The aim of this study based on frequency respiratory apnea in patients with acute tramadol poisoning hospitalized in Farshchian Hospital of Hamadan, Iran from Jan 2014 to Dec 2015. Methods: All patients with tramadol poisoning who hospitalized and treated at poisoning ward were enrolled into the study. Their demographic data including age, gender, drug ingestion dose, and respiratory apnea leading to taking naloxone or intubation collected and analyzed statistically by SPSS software. Results: Overall, 350 patients aged between 14 to 68 yr old were investigated. About 75 of them were male and among them, 81.14 had deliberate self-poisoning. 4.86 developed apnea whose average tramadol consumption was 4158.83 mg. In patients who had not apnea, the average tramadol consumption was 122.38 mg, that was statistically significant difference (P<0.001). Conclusion: Although apnea development frequency in patients with excessive tramadol ingestion is rare, it is significant as a potentially life-threatening risk, occasionally ignored.

Cardiac arrest from tramadol and fentanyl combination.

Sir, Tramadol is a centrally acting atypical opioid analgesic commonly used in the treatment of moderate to severe pain. It has a low affinity to μ opioid receptors and also inhibits the reuptake of serotonin and norepinephrine. Fentanyl is a potent, synthetic opioid with a rapid onset of action and strong affinity to μ receptor. Both the drugs are considered to have a high safety profile and used widely in anaesthesia. Fentanyl and tramadol impair presynaptic reuptake of serotonin and in combination with other serotonergic medications can cause serotonin syndrome. We report a case where premedication with the two drugs in therapeutic doses led to serotonin syndrome with severe life-threatening cardiac arrhythmia. A 43-year-old male American Society of Anaesthesiologists physical status1 patient, with radicular pain was scheduled for C5–6 anterior cervical discectomy. He was on gabapentin 150 mg tid and ibuprofen 200 mg bid for pain relief since 1 month. Preanaesthetic evaluation had been insignificant, and and so was the examination prior to shifting into the theatre. After connecting standard monitors and preoxygenation, intravenous (i.v.) fentanyl 50 μg (0.83 μg/kg, in dilution of 1 ml = 50 μg) was administered. Patient was agitating, and pain was thought to be the cause of his agitation. For the fear of developing chest wall, rigidity another agent was considered instead of higher doses of fentanyl. I.v. tramadol 75 mg (1.25 mg/kg, in dilution of 1 ml = 20 mg) was administered slowly over 2–3 min. Immediately a supraventricular rhythm (SVT) with a rate of 180/min and ventricular ectopics were noted on the monitor. It soon deteriorated to ventricular tachycardia (VT) and then into ventricular fibrillation (VF). Cardiopulmonary resuscitation (CPR) was initiated, and airway was secured with endotracheal intubation. Defibrillation with biphasic mode (200 J) was administered thrice during the CPR cycle without sustained sinus rhythm. Injection amiodarone 300 mg bolus was administered after 3rd shock after which sustained sinus rhythm was achieved. After initiating maintenance amiodarone infusion (0.5 mg/kg/h for 24 h) and vasoactive support (noradrenaline and adrenaline infusion at 20 mcg/min) patient was shifted to the intensive care unit (ICU). In the ICU, ventilation was continued for a day with midazolam and morphine for sedation and analgesia. A bedside echocardiogram revealed a good cardiac contractility and output. Induced hypothermia at 34°C was maintained for the day. The next day vasoactive drugs were weaned off, and the patient was awake and successfully extubated. Amiodarone was changed to oral mode of administration and patient was discharged to the ward on 2nd day. The combination of tramadol and fentanyl for premedication is seldom used. The combination has improved tolerance for awake endotracheal intubation[1] and has reduced the incidence of supraventricular arrhythmia in patients undergoing pulmonary resection.[2] Fentanyl associated fatalities have been primarily due to respiratory depression as even low concentrations lead to it.[3] Life-threatening central nervous system (CNS) and cardiac complications are generally found after tramadol ingestion at high doses with unintentional or intentional suicidal attempts. Ahmadi et al., after analysing the cases of tramadol intoxication found mortality rate of 0.97%. Most of the cases have been reported in conjunction with other drugs such as CNS depressants.[4] However, Shadnia et al., reported two fatalities with tramadol intoxication without any co-ingestions.[5] In therapeutic doses, both tramadol and fentanyl have been implicated in serotonin toxicity though tramadol is more notorious for severe toxicity.[6] Serotonin toxicity is marked by the triad of neuromuscular excitation, autonomic stimulation and changes in mental state. Based on the clinical profile we suspected serotonin syndrome to be causative for the complication in our patient. The features of toxicity from drug combination develop rapidly after onset of effective blood levels of the second drug. The autonomic features such as tachycardia and tachypnea are not usually severe.[6] In our patient, the administration of i.v. fentanyl initiated the toxicity features (agitation) which became more pronounced with tramadol dose. However, the cardiac signs erstwhile considered not to be of serious consequence, in our patient caused near fatal arrhythmia. The rhythm quickly transformed from SVT to VT and then to VF [Figure 1]. No role of use of gabapentin preoperatively in this peroperative drug interaction between fentanyl and tramadol could be explained. Figure 1 Electrocardiogram tracing of the rhythm during cardiopulmonary resuscitation To our knowledge and belief, this is the first report of serotonin toxicity with tramadol and fentanyl combination, in therapeutic doses without any other serotonergic medication. The inability to monitor serum drug level has been a limitation, but the absence of any other drug administered prior to fentanyl and tramadol effectively establishes the aetiology. This case report highlights the dangers of combining two drugs with potential of serotonin toxicity and the severity of cardiac complication that can even be near fatal.

Nonfatal tramadol overdose may cause false-positive phencyclidine on Emit-II assay

False-positive results are a common finding with qualitative urine drug screens. This report describes 2 patients with positive phencyclidine (PCP) screens using the Emit II Plus Drugs-of-Abuse Test (Siemens Healthcare Diagnostics, Inc, Tarrytown, NY) after tramadol ingestion. Our first case was a 43-year-old woman with a history of bipolar disorder who presented to the emergency department(ED) for medical clearance after ingesting an unknown amount of tramadol. Her urine drugs-of-abuse screen was positive for PCP. A comprehensive gas chromatography/mass spectrometry qualitative urine drug screen demonstrated valproic acid metabolites, nicotine, gabapentin, benztropine, and a large peak of tramadol. Our second case was a 3-year-old boy with a medical history of previous ingestions presented to the ED for altered mental status and suspected ingestion. His urine drugs-of-abuse screen was positive for PCP. A comprehensive gas chromatography/mass spectrometry qualitative urine drug screen demonstrated a large peak of tramadol. Molecular similarity analysis can predict cross-reactivity of drug of abuse and therapeutic drug monitoring assays. This computational analysis demonstrated that tramadol and its metabolite possess enough similarity to PCP to produce positives due to interaction with the assay antibody (or antibodies). Tramadol and its metabolites can cause a false-positive Emit II+ PCP screen, and clinicians should use caution when interpreting urine drugs-of-abuse screens that use immunoassays.

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

Tramadol is a synthetic, centrally acting analgesic for the treatment of moderate to severe pain. The marketed tramadol is a racemic mixture containing 50% (+)tramadol and 50% (-)tramadol and is mainly metabolized to O-desmethyltramadol (M1) by the cytochrome P450 CYP2D6. Tramadol is generally considered to be devoid of any serious adverse effects of traditional opioid receptor agonists, such as respiratory depression and drug dependence. A 22-year-old Caucasian female patient was admitted to our ICU in refractory cardiac arrest requiring extracorporeal membrane oxygenation. This aggressive support allowed resolution of multi-organ dysfunction syndrome. Repeated blood analyses using liquid chromatography-tandem mass spectrometry confirmed high concentrations of both tramadol and its main metabolite O-desmethyltramadol. Genotyping of CYP2D6 revealed the patient to be heterozygous for a duplicated wild-type allele, predictive of a CYP2D6 ultrarapid metabolizer (UM) phenotype, confirmed by calculation of the tramadol/M1 (MR1) metabolic ratio at all time points. We here report a case of near-fatal isolated tramadol cardiotoxicity. Because of the inhibition of norepinephrine reuptake, excessive blood epinephrine levels in this CYP2D6R UM patient following excessive tramadol ingestion could explain the observed strong myocardial stunning. This patient admitted intermittent tramadol consumption to gain a "high" sensation. In patients with excessive morphinomimetic effects, levels of tramadol and its main metabolite M1could be measured, ideally combined with CYP2D6 genotyping, to identify individuals at risk of tramadol-related cardiotoxicity. Tramadol treatment could be optimized in these at-risk individuals, consequently improving patient outcome and safety.

Quantification in Postmortem Blood and Identification in Urine of Tramadol and Its Two Main Metabolites in Two Cases of Lethal Tramadol Intoxication

Tramadol is an opioid analgesic considered to induce fewer side effects than other compounds of this class. It has been extensively prescribed for two decades. However, serious complications may occur in case of intoxication. We report here two cases of fatal intoxication due to tramadol ingestion. Tramadol, O-desmethyltramadol (ODT), and N-desmethyltramadol (NDT) were quantitatively and qualitatively determined in postmortem blood and urine, respectively. An HPLC method coupled with fluorescence detection was validated using total error approach for the analysis of tramadol, ODT, and NDT in blood. In case 1, concentrations of tramadol and its metabolites were 7.7 mg/L (tramadol), 1.33 mg/L (ODT), and 0.6 mg/L (NDT). In case 2, concentrations found were 48.34 mg/L (tramadol), 2.43 mg/L (ODT), and 10.09 mg/L (NDT). The tramadol concentration found in case 2 is one of the highest ever described in the literature. Opposite ratios of ODT/NDT concentrations observed in different cases were suggested to be useful for the evaluation of the delay between ingestion and death. However, the changes in metabolites levels may also be explained by pharmacokinetic interactions and quantitative differences in the activity of the cytochrome-P450 2D6. Interestingly, norfluoxetine was detected in subtherapeutic levels in case 2. Most of these aspects in tramadol-related fatalities are reviewed in this paper, and an overview of fatal intoxications due to tramadol is presented.

Two separate dose-dependent effects of paroxetine: mydriasis and inhibition of tramadol’s O-demethylation via CYP2D6

To investigate paroxetine's putative dose-dependent impact on pupil reaction and inhibition of the O-demethylation of tramadol. Twelve healthy CYP2D6 extensive metabolizers participated in this double-blinded randomized five-way placebo controlled cross-over study; they received placebo, 10, 20, 30, and 50 mg paroxetine as single oral doses at bedtime. Next morning the pupil was measured followed by oral intake of 50 mg of tramadol, and urine was collected for 8 h. Three hours after ingestion of tramadol a second measurement of the pupil was performed. Enantioselective urine concentrations of (+/-)-tramadol and (+/-)-O-desmethyltramadol (M1) were determined. With placebo, the median maximum pupil diameter was 6.43 mm (range 5.45-7.75 mm) before tramadol and 6.22 mm (4.35-7.65 mm) after 50 mg of tramadol (P = 0.4935). Paroxetine resulted in a statistically significant, dose-dependent dilatation of the pupil with a geometric mean difference of 1.17 (95% CI 1.10-1.24) after ingestion of 50 mg paroxetine (P < 0.001). Likewise, a reduction in the relative constriction amplitude with a geometric mean difference of 0.81 (95% CI 0.71-0.92) (P < 0.001) was seen. A dose-dependent inhibition of the metabolism of tramadol by an increase in the two urinary metabolic ratios (+)-tramadol / (+)-M1 [geometric mean difference 9.09, 95% CI 5.60-14.73 (P < 0.001)] and (-)-M1 / (+)-M1 [geometric mean difference 2.84, 95% CI 2.15-3.77 (P < 0.001)] was also observed. Paroxetine is a dose-dependent dilator of the pupil and as expected a dose-dependent inhibitor of (+)-tramadol's O-demethylation.

Dose-independent occurrence of seizure with tramadol

Tramadol, as a centrally-acting, opioid-like analgesic with serotonin reuptake inhibition property, is one of the most prescribed analgesics in the world. We assessed the incidence of seizure, as it is one of the most important adverse effects. In a cross-sectional study, 215 cases of tramadol users or abusers who were admitted to Loghman-Hakim Hospital Poisoning Center (LHHPC) in Tehran during a 5-month period, from April 2007 to September 2007, were assessed to evaluate the occurrence of seizure. Patients with positive history of co-ingestion of other drugs, addiction, convulsive disorders, renal diseases, or head trauma with abnormal electroencephalography (EEG) or computerized tomography (CT) scan of the brain were excluded, thus 132 patients were included in the study. For patients who had seizure, CT scan of the brain and EEG were performed, and frequency and type of seizure were identified. Mean tramadol dose was compared between patients with and without seizure. Among the patients, 97 (73.5%) were male. Seizure occurred in 61 patients (46.2%) within 24 hours after tramadol ingestion. The majority of patients who had seizure were male (male, 83.6% vs. female, 16.4%). Mean tramadol dose was lower among females than males (males, 2413 mg vs. females, 1706 mg), but the difference was not statistically significant. Of 35 patients with documented seizure type, all showed generalized tonic-clonic seizure and 12 patients had abnormal EEG (35.3%). No statistically significant difference was observed in mean tramadol intake between patients with or without seizure. Analysis of patients with seizure, according to tramadol intake, indicated that most patients used tramadol in the dose range of 500-1000 mg followed in occurrence by 1500-2000 mg, then 100-500 mg, 2500-3000 mg, and 3500-4000 mg. Mean tramadol intake does not differ between patients with and without seizure, and the most common dose range in those with seizure is 500-1000 mg. We thus conclude that the incidence of seizure with tramadol is not dose dependent.

Pediatric Tramadol Ingestion Resulting in Seizurelike Activity

Tramadol has been reported to cause seizures in therapeutic dosing and in overdose. We present a series of 2 infants poisoned with tramadol, both presenting with abnormal neurologic findings: either seizures or seizurelike activity. Tramadol poisoning should be considered in the differential diagnosis of dystonia and seizures.

Determination of Opioid Analgesics in Hair Samples Using Liquid Chromatography/Tandem Mass Spectrometry and Application to Patients Under Palliative Care

Hair testing procedures allow a cumulative reflection of long-term drug abuse and are useful as a test for compliance in clinical toxicology. In the present study, liquid chromatography coupled with tandem mass spectrometry was used to determine analgesic opioid drugs in hair samples. The procedure used a simple methanolic extraction, and the evaporated extract was analyzed directly. A selective and sensitive procedure for the simultaneous determination of bisnortilidine, nortilidine, tilidine, buprenorphine, codeine, oxycodone, fentanyl, norfentanyl, hydromorphone, morphine, normorphine, oxymorphone, methadone, piritramide, and tramadol was developed and fully validated. The method fulfilled validation criteria and was shown to be sensitive, with limits of detection ranging from 0.008 to 0.017 ng/mg hair matrix, and precision ranging between 3.1% and 14.9 %. The applicability of the method was shown by analysis of authentic hair samples from patients receiving opioids for the treatment of cancer pain (eg, fentanyl was detected in concentrations up to 0.292 ng/mg, tramadol in concentrations up to 0.612 ng/mg of hair of 1 patient). Hair analysis was shown to be a complementary and useful tool in monitoring the drug-taking behavior of patients consuming opioid analgesics for the treatment of pain. In self-reports and medical records especially, the ingestion of tramadol and methadone was found to be dramatically underreported. In summary, hair analyses gave important additional information for the medical treatment of patients, the results often coming as a surprise to even the attending physicians.

Fatal hepatic failure following accidental tramadol overdose

A case of fatal overdose of tramadol is described, occurring in a 67-year-old man with painful rib fractures who accidentally ingested more than the recommended daily dose. The mode of death was acute liver failure due to fulminant hepatic necrosis. Post-mortem toxicology was negative apart from revealing a blood tramadol concentration well above the normal therapeutic range. This is the first report of fatal tramadol ingestion occurring in a therapeutic setting and also the first tramadol-related death where the mechanism was liver failure.