Two Fatal Intoxications Due to Tramadol Alone: Autopsy Case Reports and Review of the Literature.

Since tramadol was marketed, it has been widely prescribed as a pain killer because of its relatively safe profile among opioids.Nevertheless, intoxication can occur: overdose can lead to fatal outcomes mostly in association with other drugs, via the potential interaction with serotonergic antidepressant medications, as well as the potential for increased central nervous system (CNS) depression.Fatal outcomes only attributable to tramadol are a rare entity. In this case report, 2 fatal cases are described due to tramadol stand-alone intoxication with peculiar characteristics.In case 1, gas chromatography - mass spectrometry analysis detected tramadol in all specimens (32 µg/mL in the heart blood, 23.9 µg/mL in the femoral blood, 3.3 µg/mL in the bile, and 1.4 µg/mL in the urine). No other CNS depressants were detected by toxicological analysis.In case 2, gas chromatography - mass spectrometry analysis detected tramadol in all specimens (7.5 µg/mL in the heart blood, 5.8 µg/mL in the femoral blood, and 18 µg/mL in the urine). No other CNS depressants were detected by toxicological analysis.Review of the literature was performed to clarify the actual knowledge on this topic.

[A Case of Acetaminophen Poisoning Associated with Tramcet Overdose].

Tramcet is a mixture of tramadol and acetaminophen. Acetaminophen poisoning may be caused by excessive intake of Tramcet. A 17-year-old female took excessive quantity of Tramcet before noon. She reported it herself in the emergency room. Her main complaint was nausea and dizziness. Acetaminophen may cause liver damage with dose-dependent manner. Because there was a possibility of acetaminophen poisoning, we started oral acetylcysteine. She was discharged from hospital 5 days later without side effects of acetylecysteine and liver damage.

Effects of tramadol, clonazepam, and their combination on brain mitochondrial complexes.

The present study is an unsubstantiated qualitative assessment of the abused drugs-tramadol and clonazepam. The aim of this study is to evaluate whether the effects of tramadol, clonazepam, and their combination on mitochondrial electron transport chain (ETC) complexes were influential at therapeutic or at progressively increasing doses. The study comprised of a total of 70 healthy male rats, aged 3 months. According to the drug intake regimen, animals were divided into seven groups: control, tramadol therapeutic, clonazepam therapeutic, combination therapeutic, tramadol abuse, clonazepam abuse, and combination abuse group. At the end of the experiment, brain mitochondrial ETC complexes (I, II, III, and IV) were evaluated. Histopathological examinations were also performed on brain tissues. The results showed that groups that received tramadol (therapeutic and abuse) suffered from weight loss. Tramadol abuse group and combination abuse group showed significant decrease in the activities of I, III, and IV complexes but not in the activity of complex II. In conclusion, tramadol but not clonazepam has been found to partially inhibit the activities of respiratory chain complexes I, III, and IV but not the activity of complex II and such inhibition occurred only at doses that exceeded the maximum recommended adult human daily therapeutic doses. This result explains the clinical and histopathological effects of tramadol, such as seizures and red neurons (marker for apoptosis), respectively.

[Intoxication of female patient with generalised cancer in hospital--a case report]. / Zatrucie pacjentki z uogólniona choroba nowotworowa w szpitalu--opis przypadku.

Medical errors are crucial factors influencing hospital mortality. We present a case of 79-year-old female, who was admitted to the hospital due to complications associated with advanced cancer disease. After several days of hospitalization, the woman died as a result of cancer as well as severe drugs intoxication. The investigation showed extremely high concentrations of chlorprothixen and tramadol in the. blood of the patient. This paper describes a number of medical errors made by hospital staff, of which the most significant was an inappropriate drugs policy.

Hypo and hyperglycemia among tramadol overdose patients in Loghman Hakim Hospital, Tehran, Iran.

Tramadol is a synthetic and centrally active analgesic. Hypoglycemia as another possible major side effect among abusers has not been known well. Our objective is evaluation of the Blood Glucose Level (BGL) among tramadol-overdosed patients. This prospective cross-sectional study was performed from Feb to June 2013; BGL was measured at the time of admission, 8 and 12 hours later. All patients with hypoglycemia received infusion of 0.5-1 gr/kg of hypertonic dextrose and their BGL was checked every hour until normal BGL. Patients' demographic, clinical and paraclinical data were collected. Totally, 128 patients with a mean (SD) age of 24.5 (6.9) years were recruited; 127 (99.2%) were male. Seizure occurred in 59.4% cases. Mean ± SD admission BGL was 94.88 ± 21.5mg/dL. Fourteen patients experienced hypoglycemia within 12 hours period. Hyperglycemia was experienced in 8 patients (6.25%) on admission day. There was no significant relation between the dose of tramadol and BGL. In conclusion, hypoglycemia must be considered as an important side effect of tramadol-overdose. It is suggested that serial BGL monitoring in cases of Tramadol-overdose should be done for early recognition of hypoglycemia and its timely management. Also hyperglycemia may be revealed.

[Suicidal drug overdose while receiving palliative home care: a case report]. / Suizid durch Intoxikation während einer mobilen palliativen Begleitung eines Patienten mit Bronchuskarzinom.

Suicidal thoughts are a common phenomenon in palliative care which can be seen in around 10% of the patients. There is very little knowledge about attempted and committed suicide. This article is a case report about a patient with lung cancer in a terminal state of illness who ingested drugs in a toxic dose while receiving palliative home care. This article deals with ethical issues in medical treatment and various ways of decision-making.

Tramadol-induced apnea.

BACKGROUND AND OBJECTIVES: In contrast with other opioids, there are few cases of tramadol-related respiratory depression described in the literature, and renal impairment is a proposed risk factor. The aim of this study is to determine the prevalence of and predisposing factors for tramadol-related apnea in patients referred to our center. PATIENTS AND METHODS: All patients referred to Loghman-Hakim Hospital between February 2009 and April 2010 with pure tramadol intoxication were identified retrospectively. Data collected included the patient's age, sex, ingested dose, route of exposure, reason for poisoning (acute overdose or supratherapeutic use), previous history of suicidal attempts, previous history of drug or substance abuse (including tramadol), and clinical features on admission including seizures and apnea. RESULTS: We identified 525 patients with deliberate self-poisoning (359; 68.4%) or abuse (146; 27.8%), and in 114 (21.7%) of these, there was a history of tramadol abuse. Four hundred twenty-nine (81.7%) of patients had acute poisoning and were referred to hospital within 6 hours of ingestion. Nineteen patients (3.6%) experienced apnea and received respiratory support (16; 84.2%) or naloxone administration (3; 15.8%) within 24 hours of ingestion (mean, 7.7 ± 7 hours; range, 1-24 hours). The mean dose ingested by patients experiencing apnea was 2125 ± 1360 mg (range, 200-4600 mg), which was significantly higher than those who did not experience apnea, 1383 ± 1088 mg (range, 100-6000 mg), P < .001. One death occurred in each group, which was significant (P < .001). Renal impairment was not observed in any of the patients who experienced apnea.

Complicated suicide versus autoeroticism?: a case involving multiple drugs and a porta-potty.

In this report, a unique and bizarre case of complicated suicide is presented. The decedent was found dead in the basin of a porta-potty, wearing women's pantyhose, jewelry, and makeup. The initial investigation was suspect for homicide. Although an autoerotic accidental death cannot be excluded, the patient's medical history and autopsy results provided evidence for suicide, including several substances positive in his serum. Tramadol was quantified to be 140 mg/L, approximately 470 times the therapeutic range. Moreover, formaldehyde was also present, presumably absorbed from the contents of the chemical toilet. An exhaustive search could not reveal similar circumstances of suicide in a porta-potty or with the levels of tramadol found in the decedent.

Sodium channel blockade with QRS widening after an escitalopram overdose.

INTRODUCTION: Escitalopram is rarely associated with prolongation of the QTc interval; however, there are no reported cases of QRS complex widening associated with escitalopram overdose. We report a case of a patient who presented with both QRS complex widening and QTc interval prolongation after an escitalopram overdose. CASE: A 16-year-old girl presented to the emergency department after ingestion of escitalopram, tramadol/acetaminophen, and hydrocodone/acetaminophen. Laboratory results were significant for 4-hour acetaminophen 21.1 µg/mL. Serum electrolytes including potassium, magnesium, and calcium were all normal. Initial electrocardiogram (ECG) revealed a widened QRS with an incomplete right bundle branch pattern. After administration of 100-mEq sodium bicarbonate, a repeat ECG revealed narrowing of the QRS complex and a prolonged QTc interval. Magnesium sulfate 2 g intravenous and sodium bicarbonate drip were initiated. A repeat ECG, 1 hour after the second, revealed normalization of the QRS complex and QTc interval. DISCUSSION: Prolongation of the QTc interval is an expected effect of escitalopram. Both escitalopram and citalopram are metabolized to the cardiotoxic metabolite S-didesmethylcitalopram and didesmethylcitalopram, respectively, which have been implicated in numerous cardiac abnormalities including widening of the QRS complex. Although never previously described with escitalopram, this mechanism provides a reasonable explanation for the QRS complex widening and incomplete right bundle branch block that occurred in our patient. CONCLUSIONS: Both QRS complex widening and QTc interval prolongation should be monitored in cases of escitalopram and citalopram overdoses.

Isolated tramadol overdose associated with Brugada ECG pattern.

Tramadol is a commonly prescribed synthetic opioid analgesic. In humans, electrocardiogram (ECG) changes consistent with sodium-channel blockade have not been described in overdoses with tramadol. We report a case of isolated tramadol overdose associated with a Brugada ECG pattern. A review of the literature reveals no previous human cases of tramadol overdose causing ECG changes consistent with sodium-channel blockade. However, in vitro blockade of sodium-channels has been demonstrated with high concentrations of tramadol. Tramadol overdose should be recognized as a cause for the manifestation of a Brugada ECG pattern in the setting of suicidal intoxication.

Marked and prolonged serotonin toxicity in a tramadol-poisoned patient with a pharmacokinetic study.

BACKGROUND: Tramadol poisoning rarely causes serotonin toxicity, which mechanisms remain poorly understood. We investigated alterations in tramadol pharmacokinetics in a tramadol-poisoned patient who presented with marked and prolonged serotonin toxicity. CASE REPORT: A 21-year-old male self-ingested 750 mg-tramadol, 200 mg-sotalol, 400 mg-propranolol and 6 mg-lorazepam. He was a kidney transplant patient treated with mycophenolate, tacrolimus, prednisone, and paroxetine. He developed transitory cardiovascular failure and prolonged serotonin toxicity requiring sedation, muscle paralysis, and cyproheptadine, with a favorable outcome. METHODS: We measured plasma concentrations of tramadol, M1, M2, and M5 using liquid-chromatography-tandem mass spectrometry, calculated elimination half-lives and metabolic ratios of the compounds, and genotyped cytochromes involved in tramadol metabolism. RESULTS: Elimination half-lives of tramadol (6.1 h) and M1 (7.1 h) were normal while those of M2 (26.5 h) and M5 (16.7 h) prolonged. M1 metabolic ratio (0.12) was 2-fold reduced, M2 metabolic ratio (197) 1000-fold increased and M5 metabolic ratio (0.12) normal. This metabolic profile in a patient with normal CYP2D6-metabolizer status based on genotyping supports CYP2D6 inhibition by paroxetine and propranolol, two strong mechanism-based inhibitors. Only M2 present in sufficient concentrations up to 48 h could explain the prolonged serotonin toxicity. CONCLUSION: Marked and prolonged serotonin toxicity was attributed to increased M2 production due to paroxetine- and propranolol-related CYP2D6 inhibition of tramadol metabolism.

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer.

BACKGROUND: 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. CASE REPORT: 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. DISCUSSION: 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.

[The expression of GABA(A) receptor alpha1 and GABA(B) receptor 1 in medulla oblongata solitary nucleus and ambiguous nucleus in the cases of tramadol intoxication].

OBJECTIVE: To observe the expression of GABA(A) receptor alpha1 (GABA(A)alpha1) and GABA(B) receptor 1 (GABA(B)1) in human medulla oblongata solitary nucleus and ambiguous nucleus due to tramadol-induced death. METHODS: GABA(A)alpha1 and GABA(B)1 were detected by immunohistochemical SP method in tramadol-induced death group and control group. All results were evaluated by images analysis system. RESULTS: Low expression of GABA(A)alpha1 and GABA(B)1 were detected in solitary nucleus and ambiguous nucleus in the control brain tissue. In cases of tramadol-induced death, the expression of GABA(A)alpha1 and GABA(B)1 significantly increased. CONCLUSION: The mechanism of tramadol intoxication death could be caused by respiratory depression induced by over-expression of GABA(A)alpha1 and GABA(B)1 in medulla oblongata solitary nucleus and ambiguous nucleus.

Machine learning algorithms to predict seizure due to acute tramadol poisoning.

INTRODUCTION: This study was designed to develop and evaluate machine learning algorithms for predicting seizure due to acute tramadol poisoning, identifying high-risk patients and facilitating appropriate clinical decision-making. METHODS: Several characteristics of acute tramadol poisoning cases were collected in the Emergency Department (ED) (2013-2019). After selecting important variables in random forest method, prediction models were developed using the Support Vector Machine (SVM), Naïve Bayes (NB), Artificial Neural Network (ANN) and K-Nearest Neighbor (K-NN) algorithms. Area Under the Curve (AUC) and other diagnostic criteria were used to assess performance of models. RESULTS: In 909 patients, 544 (59.8%) experienced seizures. The important predictors of seizure were sex, pulse rate, arterial blood oxygen pressure, blood bicarbonate level and pH. SVM (AUC = 0.68), NB (AUC = 0.71) and ANN (AUC = 0.70) models outperformed k-NN model (AUC = 0.58). NB model had a higher sensitivity and negative predictive value and k-NN model had higher specificity and positive predictive values than other models. CONCLUSION: A perfect prediction model may help improve clinicians' decision-making and clinical care at EDs in hospitals and medical settings. SVM, ANN and NB models had no significant differences in the performance and accuracy; however, validated logistic regression (LR) was the superior model for predicting seizure due to acute tramadol poisoning.

Trends in hydrocodone combination product exposures reported to California Poison Control System (CPCS) following DEA rescheduling.

CONTEXT: On October 6, 2014, the United States Drug Enforcement Administration (DEA) implemented a regulatory change for hydrocodone combination products (HCPs), moving them from Schedule III to II, in an effort to decrease drug overdoses. Existing research suggests this regulatory action reduced HCP prescribing and dispensing; however, there is limited research assessing its possible effects on overdoses and accidental exposures. OBJECTIVE: To analyze the changes in opioid exposures reported to the California Poison Control System (CPCS) before and after DEA rescheduling of HCPs. METHODS: We collected monthly exposure data reported to CPCS from 2012 to 2019 and conducted interrupted time series analyses to assess changes in exposures after rescheduling for HCPs, tramadol, oxycodone, morphine, codeine, fentanyl, and heroin. Additional analyses were done to assess any changes in exposures resulting in severe outcomes (moderate or major health effects). For HCPs, we also conducted logistic regressions to identify characteristics of exposures resulting in severe outcomes before and after rescheduling. RESULTS: Overall monthly opioid exposures reported to CPCS decreased after DEA rescheduling of HCPs. These decreases were significant for HCP, tramadol, and morphine (p < 0.001). Exposures significantly increased for heroin and fentanyl (p < 0.001). There were no significant changes in the share of severe outcomes attributed to HCP exposures after rescheduling. DISCUSSION: The DEA rescheduling of HCPs was associated with a significant decrease in HCP exposures and prescription opioid exposures overall, but was associated with increased fentanyl and heroin exposures. While other initiatives may have contributed to this decrease, our findings suggest that rescheduling may be a useful regulatory strategy to reduce drug exposures. CONCLUSION: DEA rescheduling of HCPs was associated with a significant reduction in prescription opioid exposures, suggesting that rescheduling high-risk drugs may be an effective strategy to improve public health.

Effect of scheduling tramadol as a controlled substance on poison center exposures to tramadol.

BACKGROUND: There is limited information on the effect of scheduling a drug as a controlled substance with comparable data from both a pre-scheduling and post-scheduling time period. OBJECTIVE: To investigate the temporal changes on poisoning cases involving tramadol in 4 states: 2 states where it has been scheduled and 2 where it is not scheduled. METHODS: Databases were searched for all cases involving tramadol reported from 2003 through 2009 at 6 regional poison centers that served Arkansas, Kentucky, Ohio, and West Virginia. To allow for comparison based on population, state population estimates were obtained from the US Census Bureau. RESULTS: Over the 7-year study period, the number of tramadol cases increased from 401 per year to 1009 cases per year. The mean annual increase in tramadol cases for all 4 states ranged from 8.8% to 14.1%. Post-scheduling in Arkansas and Kentucky, there was a mean decrease in cases of 4% and 31%, respectively. During this same period, the comparison states of West Virginia and Ohio showed a continued increase of 14% and 23%, respectively. The mean annual increase in tramadol cases per 100,000 population for all 4 states ranged from 16% to 31%. Post-scheduling of tramadol, there was an annual decrease in tramadol human exposures of 5% to 31% in Arkansas and Kentucky, respectively. During this same period, West Virginia and Ohio showed a continued annual increase of 14%. CONCLUSIONS: The decrease in the number of cases of tramadol exposure following its addition to the schedule of controlled substances in Kentucky and Arkansas suggests that adding a drug to the schedule of controlled substances may result in a decrease in poisoning exposures related to that drug.

Current trends in tramadol-related fatalities, Tehran, Iran 2005-2008.

Tramadol is a widely prescribed drug. Abuse of tramadol as well as tramadol-related deaths have been increasing in Iran. The objective of the present study is to evaluate the trends of tramadol-related deaths that occurred between 2005 and 2008 in Tehran, Iran. Biological samples obtained during the autopsy were analyzed. Tramadol was detected in 294 cases by itself or together with other drugs. The majority of the cases were young male adults. Tramadol-related deaths in 2008 were 32.5 times more than in 2005. These results suggest that tramadol-related fatalities are growing in Iran especially among substance abusers.

Efficacy and safety of naloxone in the management of postseizure complaints of tramadol intoxicated patients: a self-controlled study.

BACKGROUND AND AIMS: Tramadol has become a major cause of drug-induced seizure recently. Naloxone is reported to attenuate the seizurogenic activity of tramadol. Thus, the authors aimed to study the efficacy and safety of naloxone in the management of postseizure complaints. METHODS: This self-controlled study was conducted from August 2006 to August 2008. 59 tramadol intoxicated patients who did have postseizure complaints entered the study. After initial resuscitation and work-up, they received intravenous naloxone 0.05 mg every 3-5 min, and the presence of symptoms, presence of abnormal waves in cerebral state monitor (CSM), cerebral state index (CSI) and optical density (OD) were assessed. RESULTS: 47 participants completed the study, of whom 43 (91%) had symptom resolution after the intervention, and the presence of symptoms was significantly different before and after the intervention (p<0.001). 47 patients had abnormal waves in the CSM before the intervention, while 15 had abnormal waves in the CSM after intervention (p<0.001). The baseline mean of CSI was 81 (SD: 5.17), which was significantly increased to 92 (SD: 2.35) after naloxone injection (p<0.001). The baseline mean of OD was 7.1 (SD: 0.23), which was significantly increased to 7.7 (SD: 0.29) after naloxone injection (p<0.001). CONCLUSION: Naloxone can be considered in the management of postseizure complaints of tramadol toxicity, but further rigorous studies are needed to provide sufficient evidence to support its routine use.

[Distribution of tramadol in acute poisoned rats].

OBJECTIVE: To develop a rapid and accurate gas chromatography method and investigate the distribution of tramadol in acute poisoned rats for information of samples selection and results evaluation in forensic identification. METHODS: After an oral administration of tramadol at 1140 mg/kg (5 x LD50), concentrations of tramadol in rats' biological fluids and tissues were determined by gas chromatography. RESULTS: The limit of detection of tramadol in blood and urine was 0.1 microg/mL and the limit of detection in liver was 0.1 microg/g. The intra-day precision and inter-day precision were within 3.1% and 5.5% respectively, and the recovery of tramadol in blood was more than 98%. The average levels of tramadol displayed in descending order of heart blood, liver, peripheral blood, urine, vitreous humor, kidney, lung, spleen, heart, brain respectively. CONCLUSION: The established method could meet the requirements for toxicological analysis, and the results of the study suggest that blood, urine, liver, lung and kidney are suitable samples for forensic toxicological analysis in tramadol poisoning cases.