Tramadol

Forensic Toxicological Aspects of Tramadol

One of the most difficult parts in forensic toxicology is to interpret obtained drug concentrations. Was it therapeutic, toxic or even lethal to the particular individual that the blood sample was drawn from? Concentrations of opioid drugs are especially difficult to interpret, because of large interindividual differences in innate and acquired tolerance. Tramadol is a complex drug. Not only is it an opioid, it is also a racemic drug with the (+)- and (-)-enantiomers of the parent compound and metabolites showing different pharmacological effects. Further, it is metabolized by polymorphic enzymes, which may affect the amounts of metabolites formed and possibly the enantiomer ratios of the parent compound and its metabolites. It has been speculated that particularly the (+)/(-)-enantiomer ratio of O-desmethyltramadol is related to the risk of adverse effects, and it has been shown that the ratio is affected by CYP2D6 genotype. The overall aim of the thesis was to evaluate if forensic interpretations of tramadol, regarding toxicity and time since drug administration, may be improved by the use of genotyping and enantioselective concentration determination of tramadol and its three main metabolites. To simultaneously quantify the enantiomer concentrations of tramadol, Odesmethyltramadol, N-desmethyltramadol and N,O-didesmethyltramadol in whole blood, a liquid chromatography tandem mass spectrometry (LCMS/MS) method was developed and validated. Genetic variation in CYP2D6, CYP2B6, CYP3A4 (encoding the tramadol metabolizing enzymes), ABCB1 (encoding a transport protein) and OPRM1 (encoding the ?-opioid receptor) was investigated, using pyrosequencing, xTAG, and TaqMan analysis. The methods were applied to the blood samples of two study populations; 19 healthy volunteers administered a therapeutic, single tramadol dose, and 159 tramadol positive autopsy cases. The most important finding was the positive correlations between all four enantiomer ratios and time since tramadol administration in the healthy volunteers. All enantiomer ratios except the one of tramadol was also affected by the CYP2D6 genotype, which was apparent among the autopsy cases as well. Genetic variation in CYP2D6 and possibly CYP2B6 was shown to have an impact on tramadol pharmacokinetics, although no association to neither drug related symptoms nor tramadol related causes of death was found. Tramadol intoxications were predominantly characterized by low age (median 26 years) and male sex, often with a history of substance abuse and with other drugs (at fairly low concentrations) detected in blood. In conclusion, enantiomer concentration determination combined with genotyping seems promising regarding estimations of time since drug administration, although is of low value concerning interpretations of toxicity in autopsy cases.

Current Therapy in Pain

This unique resource focuses on the diagnosis and treatment of painful conditions-both acute and chronic-from a multi-disciplinary perspective. Joined by a team of nearly 200 international contributors representing a wide range of specialties, Dr. Smith presents the best management options within and across specialties. Succinct treatment and therapy guidelines enable you to quickly access clinically useful information, for both inpatient and outpatient pain management, while a 2-color format enhances readability and ease of use and highlights key concepts. And, as an Expert Consult title, it includes access to the complete contents online, fully searchable, plus links to Medline and PubMed abstracts-providing rapid, easy consultation from any computer! Includes access to the complete text online, fully searchable, plus links to Medline and PubMed abstracts-providing quick and convenient reference from anyplace with an Internet connection. Offers a cross-discipline approach to pain management for a comprehensive view of the best treatment options within and across specialties including internal medicine, gynecology, physical medicine and rehabilitation, orthopedics, and family medicine. Provides succinct treatment and therapy guidelines, enabling you to locate useful information quickly. Organizes guidance on acute and chronic therapies in a templated format, to facilitate consistent, quick-access consultation appropriate for inpatient or outpatient pain management. Features a 2-color format that enhances readability and ease of use and highlights key concepts. Your purchase entitles you to access the web site until the next edition is published, or until the current edition is no longer offered for sale by Elsevier, whichever occurs first. If the next edition is published less than one year after your purchase, you will be entitled to online access for one year from your date of purchase. Elsevier reserves the right to offer a suitable replacement product (such as a downloadable or CD-ROM-based electronic version) should access to the web site be discontinued.

Effects of Intravenous Tramadol in Horses