Tramadol is a widely used analgesic opioid for moderate-to-severe pain due to its efficacy and safety. Although tramadol induces less adverse effects compared with other opioids, an increased post mortem distribution tramadol of documented cases of dependence, abuse, intentional overdose or intoxication have been described.

post mortem distribution tramadol

Tramadol is a widely used analgesic opioid for moderate-to-severe pain due to its efficacy distribution tramadol safety. Although tramadol induces less adverse effects compared with other opioids, an increased number of documented cases of dependence, abuse, intentional overdose or intoxication have been described. In fatal intoxication, the interpretation of the probable cause of death often relies on the measurement of the tramadol concentration in blood.

However, postmortem redistribution PMR may affect the results and therefore bias the autopsy report. In the present study, the postmortem cardiac and femoral blood samples from 15 cases of fatal tramadol intoxication were obtained to assess the PMR of tramadol and its main active metabolite, O -desmethyltramadol M1. Toxicological analysis was performed by the gas chromatography—electron impact-mass spectrometry GC—EI-MS method, previously developed and validated for the quantification of both analytes.

The cardiac-to-femoral blood ratios of 1. Results were compared with those in the literature and it was possible to conclude that femoral blood should be considered for quantitative interpretations in fatal cases of tramadol intoxication. Tramadol is a widely used therapeutic distribution tramadol to other opioid analgesics since it has low potential for abuse, dependence and tolerance, and low probability to cause adverse effects, including respiratory depression 1.

However, the number of cases reporting dependence, abuse, intentional overdose or intoxication by tramadol is increasing. Fatal intoxications due to tramadol alone also exist, but are not common 2—6. The administration of toxic doses of tramadol concomitantly with other central nervous system depressants is one of the most common causes of severe or lethal acute intoxication 7— Tramadol is a centrally acting opioid analgesic, which has a dual mechanism of action: After oral administration, tramadol is rapidly and almost completely absorbed Using a rodent model, Bamigbade and Langford 17 demonstrated that tramadol was particularly distributed into the lungs, spleen, liver, kidneys and brain.

Tramadol is mainly metabolized in the liver by Xanax for sleep paralysis - and N -demethylation, catalyzed by the cytochrome P mainly isoenzyme CYP2D6and followed by conjugation with glucuronic acid and sulfate. The primary metabolites O -desmethyltramadol M1 and Tramadol -desmethyltramadol M2 may be further metabolized to three additional secondary metabolites namely, NN -didesmethyltramadol M3NNO -tridesmethyltramadol M4 and NO -didesmethyltramadol M5but several other metabolites have also been described 1618— The elimination half-lives of tramadol and M1 are 6.

After fatal intoxications, drug concentrations may vary according to the sampling site and the interval between death and postmortem specimen collection 26"distribution tramadol" These site- and time-dependent variations are designated as postmortem redistribution PMR Different mechanisms distribution tramadol PMR of drugs can occur: These mechanisms may be affected by the drug's lipophilicity, volume of distribution and pH The release of basic drugs from solid tissues distribution tramadol the blood compartment within some hours after death can occur due distribution tramadol a decrease in blood pH, which may be responsible for a return of the basic molecules into this compartment, due to an increased concentration gradient in nonionized forms The putrefactive process may also contribute to PMR since, after death, metabolism of distribution tramadol by bacteria is possible 2731 Nevertheless, the PMR of a drug cannot be predicted based only distribution tramadol these factors.

Other factors such as the absorption route, p K a value, postmortem interval between mortem post and autopsy, dose or particular affinity of the drug for some tissues and the possibility of a residual metabolic activity in the first hours after death also must be envisaged 27 Femoral blood appears to be the specimen of choice for postmortem toxicological analysis since it is the least subject to PMR 2734 Drug tramadol in cardiac blood distribution tramadol generally higher than in femoral blood The position and manipulation of the corpse and regurgitation of distribution tramadol from the stomach into distribution tramadol airways or thoracic trauma may explain differences in postmortem blood concentrations from different anatomic places 27alprazolam end dog food For example, the contamination of airways can induce the redistribution of drugs into the cardiac blood via the pulmonary vessels 36 Drugs that are also more concentrated in the liver, lungs or myocardium redistribute more quickly into cardiac blood, causing an increase is it safe to take klonopin and vicodin their concentrations However, in a few cases, femoral blood concentrations were found to be higher than cardiac blood concentrations.

This can occur in cases where resuscitation was attempted, presumably causing a shift of cardiac blood into the femoral vessels 2738 The difference between the cardiac and femoral vessels is known as the cardiac-to-femoral blood ratio Drugs with higher ratios have a great potential for redistribution This work aimed at the optimization and validation of an analytical method for the quantification of tramadol and M1 by distribution tramadol chromatography—electron impact-mass spectrometry GC—EI-MS to evaluate the PMR of these analytes in postmortem cardiac and femoral blood samples from 15 cases of suspected fatal tramadol intoxication.

It is expected that distribution tramadol obtained results will help to define the best conditions of blood collection for the measurement of tramadol and M1 in fatal cases resulting from tramadol intoxications. According to the current Portuguese law for medico-legal autopsies and following the ethical principles of Declaration of Helsinki, no informed written or oral consent of the victim's family is required for scientific research in routinely collected samples.

Therefore, the use of these samples beyond establishing the cause of death is foreseen by the law. Phenacetin [ N - 4-ethoxyphenyl acetamide; molecular mass O -Desmethyltramadol hydrochloride [M1, 3- 2- 1-aminomethylethyl hydroxycyclohexyl phenolhydrochloride ; molecular mass All the reagents used were of analytical grade or from the highest available grade.

Postmortem cardiac and femoral blood samples 1. Samples were collected according to the Institutional rules and previously proposed guidelines Working standard solutions tramadol in hepatic impairment tramadol and M1 for the calibration curve were prepared at different concentrations by diluting stock solutions in methanol 0. Solid-phase extraction SPE was performed using solid-phase C 18 cartridges connected to a vacuum manifold and conditioned twice with 1 mL of methanol, followed by thrice with 1 mL of 0.

The supernatant was then passed through the cartridges. How much weight did you lose on phentermine 37.5 cartridges were washed twice with 1 mL of 0. After drying under full vacuum for 1 min, the analytes were eluted with 2 mL of 2-propanol. B Extraction with solid-phase extraction SPE. Tramadol and M1 are polar organic compounds with low volatility, which limits their analysis by gas chromatography.

To overcome these limitations, a derivatization step was introduced in the sample preparation procedure. In our study, tramadol and M1 derivatization was performed according to Pinho et al. The flow of the carrier alprazolam vs diazepam recreational was maintained at 1. Analyses were performed in a FullScan mode with splitless injection.

The validation of the method was performed accordingly to European Medicines Agency 43 and other authors 4244 The guidelines of the European Medicines Agency have been harmonized with the guidance by the Food and Drug Distribution tramadol 46green xanax bars street name is now generally accepted by distribution tramadol biopharmaceutical industries as the gold standard method distribution tramadol validation The limit of detection LODlower limit of quantification LLOQintra- and inter-assay precision, accuracy, recovery and linearity of the method were determined.

To obtain these validation data, calibration curves were prepared by spiking blank blood with appropriate volumes of tramadol and M1 standard solutions. Blood is the matrix of choice in toxicological analysis for the quantification of xenobiotics, since there is a good correlation between blood concentration and the toxic effect, and is a useful specimen to establish acute ingestion However, it is a complex biological matrix, with the presence of many interferents, in particular, proteins, hormones, blood cells and possible clots.

The separation of the analytes of tramadol from the matrix and elimination of possible interferents is crucial for subsequent chromatographic klonopin withdrawal symptoms depression. Nevertheless, few methods have focused on the inherent problems associated with postmortem specimens, particularly blood, which is frequently hemolyzed and degraded, causing column blockage and reducing extraction efficiency and recovery The regression analysis for both analytes was found to be linear in the range of 0.

The comparison of the obtained results with values of LOD and LLOQ documented in the literature 7—103649 suggests a good capacity for quantification of both analytes, even at low concentrations. The method provided an accurate and simple assay with adequate precision for the quantification of tramadol and M1 with coefficients of variation "tramadol distribution" 1.

The recovery was also evaluated and the results obtained indicated an efficient clean-up procedure, with extraction recovery rates of Preliminary tests were performed to determine the best conditions of chromatographic separation and detection in order to obtain the best peak resolution and separation of tramadol and M1. The study of chromatographic conditions revealed the presence of two peaks for each analyte.

Based on the fragmentation pattern of each peak produced by electron impact-mass spectrometry, for tramadol, the first peak corresponds to tramadol derivatized and the second peak post mortem tramadol nonderivatized, with retention times of In the M1 case, the first and second peaks correspond to M1 di-derivatized The IS chromatogram exhibited only one peak "mortem distribution post" nonderivatizedwith a retention time of 8.

Quantitative analysis was performed taking into account some target or qualifier ions: The PMR of tramadol and M1 determinations were evaluated in postmortem cardiac and femoral blood samples from 15 cases of suspected fatal tramadol intoxication. The analysis of femoral blood samples revealed concentrations ranging from 0. Cardiac blood samples concentrations ranged from 0.

According to the literature, therapeutic blood concentrations of tramadol in adults range from 0. Toxic concentrations of tramadol have distribution tramadol reported to be 0. Until now, therapeutic and toxic concentrations for the M1 metabolite have not been described. Moreover, comparing the concentrations of the parent drug and its metabolite M1it is possible to obtain information on whether the drug was chronically or acutely ingested 9.

High concentrations of tramadol and low metabolite concentrations are indicative distribution tramadol acute intoxication because, before excretion, tramadol is mainly metabolized by the cytochrome P isoenzyme CYP2D6 in M1 9 In this study, tramadol concentrations were higher than those of the M1 metabolite, as previously described in other studies 3133652 Concentrations distribution tramadol tramadol and M1 in postmortem femoral and cardiac blood samples of 15 intoxication cases.

Nevertheless, tramadol has low-to-moderate PMR and this is relatively uniform in all organs and blood with the exception of urine 581013 In urine, distribution tramadol concentration of distribution tramadol mortem post is generally higher than in blood 48distribution tramadol13 The concentration of tramadol in the liver and kidneys, compared with that in blood, does not suggest a major sequestration of distribution tramadol drug 458.

In cases of tramadol intoxication, postmortem arterial blood concentrations are often higher than in venous blood concentrations 4810 In the brain, the tramadol concentration is similar to that in femoral blood, with little PMR 10 However, the lipophilicity "distribution tramadol" its distribution and penetration into the central nervous system distribution tramadoland therefore, the M1 metabolite concentration is lower than distribution tramadol parent compound in this tissue.

M1 has a higher polarity lower lipophilicity than tramadol and does not penetrate the blood—brain barrier to the same extent as tramadol 16 PMR distribution tramadol, thus, complicate the interpretation of analytical data in forensic toxicology and make difficult the determination of the cause of death 27 Tramadol and metabolite concentrations in cases of tramadol-related deaths and tramadol intoxication.

The differences observed in this study between femoral and cardiac blood concentrations are partly due to the physicochemical properties of tramadol and M1. Both analytes are organic bases with similar molecular structures and p K a values 9. Nevertheless, tramadol has a higher lipophilicity coefficient log D 7. Perhaps due to this fact, higher tramadol concentrations were found in cardiac than in the femoral blood, and the M1 concentrations were identical in cardiac and femoral blood, which shows that tramadol has a greater PMR.

However, the cardiac-to-femoral blood ratios for tramadol and M1 are 1. These xanax for ibs pain are consistent with those obtained in other published studies for tramadol and M1. Musshoff and Madea 4 obtained a ratio of 1.