Actions of tramadol, its enantiomers and principal metabolite, O-desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus.

Stamford JA.

Department of Anaesthesia, St Bartholomew's Hospital, London.

Tramadol is an atypical centrally acting analgesic agent with relatively weak opioid receptor affinity in comparison with its antinociceptive efficacy. Evidence suggests that block of monoamine uptake may contribute to its analgesic actions. Therefore, we have examined the actions of (+/-)-tramadol, (+)-tramadol, (-)-tramadol and O-desmethyltramadol (M1 metabolite) on electrically evoked 5-HT efflux and uptake in the dorsal raphe nucleus (DRN) brain slice, measured by fast cyclic voltammetry. Racemic tramadol and its (+)-enantiomer (both 5 mumol litre-1) significantly blocked DRN 5-HT uptake (both P < 0.05) and increased stimulated 5-HT efflux (P < 0.01 (+/-)-tramadol; P < 0.05 (+)-tramadol). The (-)-enantiomer and metabolite, O-desmethyltramadol, were inactive at the concentration tested (5 mumol litre-1). For both (+/-)-tramadol and the (+)-enantiomer, the action on 5-HT efflux preceded an effect on 5-HT uptake, suggesting that uptake block was not the cause of the increased 5-HT efflux and that tramadol might therefore have a direct 5-HT releasing action. This activity, at clinically relevant concentrations, may help to explain the antinociceptive efficacy of tramadol despite weak mu opioid receptor affinity and adds to evidence that tramadol exerts actions on central monoaminergic systems that may contribute to its analgesic effect.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9389855&dopt=Abstract tramadol



Identification of tramadol and its metabolites in blood from drug-related deaths and drug-impaired drivers.

Christian GD.

Washington State Toxicology, Department of Laboratory Medicine, University of Washington, Seattle 98134, USA.

Tramadol is a centrally acting, binary analgesic that is neither an opiate-derived nor a nonsteroidal anti-inflammatory drug and that was approved for use in the United States in 1995. It is used to control moderate pain in chronic pain settings such as osteoarthritis and postoperative cases. Used in therapy as a racemic mixture, the (+)-enantiomer weakly binds to the mu-opioid receptor, and both enantiomers inhibit serotonin and norepinephrine reuptake. Tramadol's major active metabolite, O-desmethyltramadol (ODT), shows higher affinity for the mu-opioid receptor and has twice the analgesic potency of the parent drug. The synergism of these effects contributes to tramadol's analgesic properties with the (+)-enantiomer exhibiting 10-fold higher analgesic activity than the (-)-enantiomer. Although tramadol was initially thought to exhibit low abuse potential, Ortho-McNeil, the drug's manufacturer, recently reported a large number of adverse events attributed to tramadol including abuse by opioid-dependent patients, allergic reactions, and seizures. The high number of adverse reactions has prompted the company to update the prescribing information for the drug. An analytical method using gas chromatography-mass spectrometry (GC-MS) without derivatization for the determination of tramadol and its metabolites is reported. An n-butyl chloride extraction is followed by GC-MS analysis using a 5% phenylmethylsilicone column (30 m x 0.32-micron i.d.). Analysis of 12 blood samples from tramadol-related deaths and four nonfatal intoxications involving tramadol revealed concentrations ranging from 0.03 to 22.59 mg/L for tramadol, from 0.02 to 1.84 mg/L for ODT, and from 0.01 to 2.08 mg/L for N-desmethyltramadol. Three deaths were clearly attributable to acute morphine toxicity, one was a doxepin overdose, and six were multiple drug overdoses. The role of tramadol in each death is explored.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9399121&dopt=Abstract tramadol



[Tramadol in elastomeric continuous perfusion for analgesia after gynecologic surgery]

[Article in Spanish]

Gonzalez-Machado JL.

Servicio de Anestesia-Reanimacion y Unidad del Dolor, Hospital Clinico Universitario San Juan de Alicante.

Quality of analgesia provided by continuous infusion of tramadol through an elastomeric infuser (Baxter PC1071) was studied in a group of 40 women undergoing laparotomy to treat non tumoral disease. After a loading dose of 100 mg of tramadol in the recovery room, the elastomeric infuser was connected, loaded with 300 mg of tramadol in 48 ml of saline. The patient was then transferred to the ward. Analgesic quality was assessed on a visual analog scale (VAS) of 1 to 10 and on a semantic scale. Side effects, the need for supplemental analgesia and the opinion of the nurse were all recorded. The highest VAS score in the 24 h period was 2.69. Pain was described as slight by 52.5% of the women, moderate by 12.5% and absent by 35%. The main side effects were nausea and vomiting (12.5%). Three patients needed supplementary analgesia. The technique was described by 85% of the nurses as good (62.5%) or very good (22.5%). Elastomeric infusers are an effective way to deliver analgesics, and tramadol proved to be a valid analgesic for continuous infusion.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9424689&dopt=Abstract tramadol



Polymorphic CYP2D6 mediates O-demethylation of the opioid analgesic tramadol.

Dengler HJ.

Department of General Internal Medicine, University of Bonn, Venusberg, Germany.

OBJECTIVE: This study was designed to investigate whether the in vivo metabolism of tramadol was influenced by CYP2D6 polymorphism. METHODS: The extent of tramadol O- and N-demethylation was calculated by determining the amounts of tramadol and O- and N-desmethyltramadol in 24 h urine after ingestion of a test dose of tramadol. The O- and N-demethylation rates were calculated by dividing the 24-h urinary excretion amount of tramadol by that of O- and N-desmethyltramadol. Volunteers were phenotyped for CYP2D6 polymorphism using sparteine as an in vivo probe. RESULTS AND CONCLUSION: High correlation was found between tramadol-O-demethylation and sparteine oxidation in 71 extensive metabolizers of sparteine (rs = 0.544). The mean metabolic ratio of tramadol O-demethylation was significantly higher in poor metabolizers of sparteine than in extensive metabolizers (4.4 vs 0.8). These in vivo results confirm that tramadol O-demethylation is carried out to a large extent by the polymorphic CYP2D6.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9476037&dopt=Abstract tramadol