Blood Tramadol Research Articles

Development, Physicochemical Characteristics and Pharmacokinetics of a New Sustained-Release Bilayer Tablet Formulation of Tramadol with an Immediate-Release Component for Twice-Daily Administration.

There are some potential concerns about the currently marketed solid oral dosage forms of tramadol, including decreased adherence to immediate-release (IR) formulations due to the high number of doses taken each day and the slow rise in the blood tramadol concentration after administration of sustained-release (SR) formulations, which may not achieve a rapid analgesic effect. To overcome these potential concerns, a twice-daily double-layered tablet formulation of tramadol comprising IR and SR layers was developed. This article reports studies that assessed its physicochemical and pharmacokinetic properties. Dissolution tests of five bilayer tablet formulations (designated tablets A-E) and pharmacokinetic studies of tablets A and B were conducted to investigate the appropriate ratio of the IR/SR layers in the double-layered tablet. Additionally, pharmacokinetic studies of three finished dosage formulations (tablets C-E) were performed in healthy adult males to investigate the effect of food intake on drug absorption. Adjusting the excipients and tramadol content in the IR and SR layers of tablets A-E altered their dissolution profiles in a manner that could be predicted based on their compositions. The IR layer was released within 15min, and the SR layer was slowly released over 10h. In the pharmacokinetic study, the time to maximum plasma concentration (tmax) of tramadol after administration of tablets A (IR:SR: 20:80mg) and B (40:60mg) was shorter than that of a commercially available SR tablet, and the half-life (t1/2) was longer than that of a commercially available IR tablet. For tablets C-E, administration after food did not affect the area under theconcentration-time curve (AUC) or maximum drug concentration (Cmax) of tramadol, but the tmax was prolonged by about 1 h compared with administration in fasting conditions. The mean ± standard deviation tmax and t1/2 for tablet D (IR:SR: 35:65 mg) in the fasting condition was 1.09 ± 0.56h and 7.82 ± 0.85h, respectively. The respective values in the fed condition were 2.47 ± 1.06h and 7.12 ± 0.85h, respectively. To address the potential concerns regarding existing formulations of tramadol, a twice-daily, extended-release bilayer formulation of tramadol consisting of an IR and SR layer was developed. Pharmacokinetic studies confirmed that the plasma tramadol concentration increased quickly after administration and was maintained over a long period of time.

Incidence and Factors Influencing Acute Tramadol Toxicity-Inducing Seizures in Damietta Governorate

An increased rate of seizures due to tramadol poisoning has been observed. However, the actual incidence and related factors are not well-studied. The purpose of this work was to investigate the relationship between the incidence of seizures and plasma tramadol level in patients with tramadol-inducing seizures. In addition, we reported the pattern of tramadol overdoses in selected patients. The study was conducted from 1st January 2017 to 28th February 2018. It involved 102 cases who recruited from toxicological units of AlAzhar University Hospital (New Damietta). After free informed consent to contribute in this study and within one hour after arrival to a toxicological unit, 10 mL of blood were separated and the serum was used for extraction of tramadol residues by using a highperformance liquid chromatography (HPLC) and other blood samples were stored at _ 8oC for the following assays to all patients; fasting blood sugar, hemoglobin levels, serum urea, serum creatinine and liver enzymes. Then clinical examination to all patients included vital signs with a special attention to central nervous system (CNS) manifestations, gastrointestinal (GIT) manifestation. The frequency of seizures (27.4%) with acute tramadol poisoning in humans is not dose dependent and seizures occurred with therapeutic doses and there were no relation between blood tramadol level and seizures. We concluded that risk of seizures increase in cases took other drugs with tramadol as alcohol and heroin. The frequency of seizures is not dose dependent; seizures occurred with therapeutic doses.

A Study of Clinical and Laboratory Picture of Acute Tramadol Toxicity in Damietta Governorate

Increased rate of seizures and respiratory complications due to tramadol poisoning have been observed, even with first time of tramadol intake. So, the present work was used to investigate the clinical manifestations and laboratory investigations of acute tramadol toxicity and the correlation between toxic tramadol manifestations and blood tramadol level and laboratory parameters. A study was performed on 100 patients (80 males and 20 females) acutely intoxicated with tramadol, admitted to toxicology unit of Al-Azhar University Hospital (New Damietta) in the period from January to December 2017. Informed consent, urine sample was collected and 10 mL of blood was separated and used for extraction of tramadol residues by using a high-performance liquid chromatography (HPLC) and other blood samples were stored at-8°C for routine investigations. Then a detailed clinical examination was done to all patients. Generally, the frequency of seizures was (46 %) with acute tramadol poisoning. There was no correlation between blood tramadol level and toxic manifestations of tramadol poisoning. So, the frequency of seizures and toxic manifestations are not dosed dependent. Cannabis was the most common co-ingested drugs and adult males were more commonly affected by tramadol poisoning. It is recommended that the drug abuse problem must be treated at the level of community problems in order to minimize medical emergencies related to acute tramadol overdose occurring mostly by addiction and further studies should be proposed to extend our knowledge about relationships between sex and seizures among tramadol intoxicated patients

Tramadol Blood Level and Prediction of Seizures in Patients with Acute Tramadol Poisoning

Tramadol is a centrally acting synthetic opioid that is widely used for its analgesic effect. Tramadol abuse is increasing in Egypt, and seizure is possible among abusers. Hence, the aim of this study was to evaluate the characteristics of acute tramadol overdosed patients and the possibility of prediction of seizures among them. Fifty participants were recruited from acutely intoxicated tramadol patients admitted to the Poison Control Center (Emergency Hospital, Tanta University) between January, 2014 and December, 2015. For each patient history, clinical data and tramadol blood level as well as urine screen were recorded. The study showed a significant difference between different groups of age, gender, tramadol dose and period of hospital stay. The majority of cases were males, between 15 and 25 years-old, who ingested a dose ranging from 1000 to 3000 mg and stayed for less than 10 hours in the hospital. The occurrence of seizures was higher among patients exposed to a tramadol dose more than 1000 mg, those who developed hyper-reflexia and those with higher blood tramadol levels. At a cut off value >600 ng/ml, blood tramadol level had a sensitivity of 73.91%, a specificity of 74.91%, positive predictive value of 70.83% and negative predictive value of 76.92%. It could be concluded that hyper-reflexia, the amount of tramadol taken and tramadol blood concentration could be used to predict the development of seizures among tramadol overdosed patients.

Cardiac arrest after tramadol injection in a polytrauma patient.

Sir, Serious adverse reactions like cardiac arrest have never been reported with isolated tramadol injection. Patient's consent was obtained for reporting this case. A 25-year-old male (65 kg) was admitted in an emergency department with right tibia and fibula fractures including ipsilateral 3–7th ribs fractures with flail chest and lung contusion. On examination, he was conscious, oriented, and hemodynamically stable but mildly tachypnic. His investigations showed normal hemogram, coagulation profile, and renal function. Urine for fat droplets and ophthalmoscopic examination did not suggest any fat globules. Focused assessed sonography for trauma was negative. Electrocardiography (ECG) was normal (QTc of 320 ms). Chest X-ray suggestive of trauma mentioned above showed no visible pneumothorax. On admission to intensive care unit, his oxygen saturation dropped to 90% with PaO281 at 40%. Failure to insert epidural catheter directed us to add tramadol 100 mg 8 hourly with paracetamol. Tramadol (Urgendol, Win Medicare Pvt. Ltd., Modipuram, India) was given 4 h after paracetamol by slow intravenous injection. Ten minutes after tramadol injection the patient developed ventricular tachycardia (VT) with hypotension [Figure 1]. Immediate cardiopulmonary resuscitation (CPR) was initiated. Patient reverted back into sinus rhythm transiently with direct current shock of 200 J but again went into VT. He was intubated, and mechanical ventilation was continued. CPR was continued and repeat shock after magnesium correction resulted into sinus rhythm. Return of spontaneous circulation took 6 min. Adrenaline infusion was initiated and titrated to treat hypotension at the rate of 0.1-0.5 mcg/kg/min. Electrolytes were corrected further. ECG after sinus rhythm showed prolonged QTc interval of 480 ms [Figure 2]. Echocardiography finding was not significant. Tramadol was discontinued and magnesium sulfate 6 g/day was added. His blood tramadol level was 11 mg/L (plasma therapeutic level 0.28-0.61 mg/L). Over next 24 h adrenaline was tapered. He was extubated on 3rd day.Figure 1: Monitor with electrocardiography showed ventricular tachycardia with hypotensionFigure 2: Electrocardiography demonstrated QTc prolongationTramadol is mainly metabolized to O-desmethyltramadol by the cytochrome P450 CYP2D6.[1] Two voltage-gated K+ channels such as rapid repolarizing current (IKr) and slow repolarizing current (IKs) are responsible for rapid and slow repolarization of cardiac muscle action potential and QT interval in the ECG paper. Rapid repolarizing current is encoded by human ether-a-go-go-related gene (HERG). A 5-hydroxytryptamine 3 (5-HT3) receptor antagonists cause cardiac arrhythmias by several mechanisms.[2] Recently, it is reported that the molecular level affinity of 5 HT3 receptor antagonist to the HERG encoded K+ channel causes prolongation of cardiac repolarization and QT prologation.[34] Tramadol inhibits 5-HT2C receptor which may be responsible for K channel related prolonged repolarisation. Blood levels of tramadol and its metabolites can be measured in any serious event. Patient with CYP2D6 genotyping is at risk of tramadol-related cardiotoxicity.[1] De Decker et al. reported tramadol intoxication patient presented with asystole and multi-organ dysfunctions.[5] In our patient, secondary survey excluded the other possibilities of pneumothorax, cardiac tamponade, fat embolism, anaphylaxis with the help of several investigations. We presumed the culprit to be tramadol with electrolytes disorder as precipitating factor. In conclusion, caution must be kept in mind using tramadol in high-risk group like patients with electrolytes disturbance and co-administration of drugs causing prolonged QTc interval in patients with CYP2D6 genotyping.

Tramadol Overdose: A Case Report

Tramadol, a commonly prescribed opioid analgesic, is considered to have a low abuse potential and devoid of side effects like drug dependence. Very few fatalities due to isolated tramadol overdose, either intentional or accidental, have been reported so far. We report a case of a 27-year-old female with isolated tramadol overdose, having a peripheral blood tramadol concentration of 4mg/L, which is exceeding the lethal blood concentration of 2mg/L. This is the first report of a patient in Singapore who survived tramadol overdose despite having a lethal blood concentration. Physicians should be aware that patients with tramadol overdose may only present with signs related to isolated Serotonin-Norepinephrine Reuptake Inhibitor (SNRI) properties and not always associated with the features of classical opioid overdose. Some patients might exhibit a certain degree of tolerance to the drug after prolonged prior exposure to the medication, and this tolerance could extend beyond the therapeutic range. It also emphasises the need for physicians to be more cautious while prescribing tramadol to their patients.

Factors Related to Seizure in Tramadol Poisoning and Its Blood Concentration

This study examines the relation between seizure and plasma tramadol concentration in patients with tramadol poisoning, as a novel centrally acting analgesic used for the treatment of mild to severe pain. All patients admitted with a history of tramadol overdose accompanied by unconsciousness or seizures referred to Baharloo Hospital Poison Center, Tehran, Iran from March 2008 to March 2009 were included. Demographic information, clinical findings, and blood tramadol concentrations were studied. There were 401 patients with a history of tramadol overdose; 121 (30.2%) with a history of seizure and 14 (3.5%) with a history of unconsciousness were included. Most of overdoses involved men (83%). The mean age was 22.9 years (range, 14-50 years). Intentional overdose was the most common mode of poisoning (51.9%). The mean dose ingested was 1,511 mg (SD, 1,353; range, 200-7,000). Mean back-extrapolated tramadol blood concentrations were 3,843 ng/mL (3,715; 269-20,049). Back-extrapolated blood concentrations were correlated with dose (r = 0.313; P < 0.001) as well as blood concentration levels (r = 0.801; P < 0.001). Seizure was significantly correlated to higher reported dose (P < 0.001) and tramadol only to overdose (P < 0.001). However, it was neither related to higher tramadol blood concentrations, nor related to time elapsed, age, sex, history of addiction, and observed Glasgow Coma Scale of patients. Most patients experienced just one seizure (76%). The tramadol-induced seizure is dose dependent. Although higher doses of tramadol was related to higher blood concentration, blood tramadol concentrations was not associated with seizure.

Distribution of metoprolol, tramadol, and midazolam in human autopsy material

In this study it was possible to measure the distribution of metoprolol, tramadol, and midazolam in human directly in several compartments. In the legal medicine autopsy material is normally investigated to find out the cause of death. But the results of corresponding toxicology measurements often involve more information. With screening methods drugs were detected without connection to the cause of death. The deceased had either a continual therapeutic treatment, a treatment during an operation, or an unsuccessful urgent therapy. A liquid/liquid extraction and a LC/MS/MS method were developed for the determination of the drug concentrations. Different autopsy materials of about 120 cases were investigated. Most frequently the drugs metoprolol, tramadol, and midazolam could be proved and determined simultaneously. Metoprolol was found in seven cases, tramadol in seven cases and midazolam in thirteen cases. The dosage of the drugs was unknown. Therefore and because of the low number of cases statistic calculations were not meaningful and an individual case study was necessary. In all cases with oral metoprolol application the patients probably took a normal customary continuous dosage. The concentrations of tramadol in blood were in the toxic range in three cases. The distribution of tramadol in the compartments was independent of the dosage. The time between oral intake of metoprolol or tramadol and death was unknown. With the distribution pattern of metoprolol in the compartments it was possible to estimate the duration between drug intake and death. In most cases midazolam was given intravenously during an operation or an unsuccessful urgent therapy. Sometimes the time between dosage and death was documented. The duration between application of the drug and death played the crucial role for the distribution of midazolam in the compartments. Measurements of drug concentrations in human autopsy material deepen the knowledge of the respective drugs’ pharmacokinetics.

Tramadol (Ultram®) Concentrations in Death Investigation and Impaired Driving Cases and Their Significance

We reviewed a series of 66 deaths in Washington State between 1995-2000 in which tramadol (Ultram and Ultracet, Ortho-McNeil) was detected in the decedent's blood, in order to assess the role tramadol was determined to have played. Additionally, we reviewed a series of 83 impaired driving cases in which tramadol was detected in order to establish a non-lethal blood tramadol concentration reference range. In both populations, tramadol was consistently found together with other analgesic, muscle relaxant, and CNS depressant drugs. Death was rarely attributable to tramadol alone. However, tramadol may be a significant contributor to lethal intoxication when taken in excess with other drugs, via the potential interaction with serotonergic antidepressant medications, as well as the potential for increased CNS depression. Although the incidence of tramadol detection has increased consistently over the last eight years, there is no evidence of a corresponding increase in the number of cases in which death was attributed solely to tramadol. Blood drug concentrations in many deaths exceeded the therapeutic serum range of 0.28-0.61 mg/L; however, the concentrations overlapped almost completely with the range identified in living subjects arrested for impaired driving. These findings suggest caution in the interpretation of blood tramadol concentrations outside of the recognized therapeutic range. It also suggests that the drug, even when used in moderate excess, is not a principle cause of death in suicidal or accidental deaths.

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.