J Pharmacol Exp Ther. 1992 Dec;263(3):1015-22.
D-16949 (anpirtoline): a novel serotonergic (5-HT1B) psychotherapeutic agent assessed by its discriminative effects in the rat.

Swedberg MD, Shannon HE, Nickel B, Goldberg SR.

Department of Health and Human Services, National Institute of Drug Abuse, Baltimore, Maryland.

D-16949 [6-chlor-2-(piperidyl-4-thio)-pyridine; Anpirtoline] is a novel centrally acting compound with serotonergic effects. To assess its discriminative stimulus effects, rats were trained to discriminate D-16949 (2.0 mg/kg i.p., 30 min) from no drug. D-16949 induced dose-dependent discriminative stimulus effects (ED50, 0.31 mg/kg), and did not produce sedation. The opioid analgesics codeine, pentazocine and tramadol all failed to substitute for D-16949. The opioid antagonist naltrexone did not antagonize the discriminative stimulus effects of D-16949. Phencyclidine, d-amphetamine, lysergic acid diethylamide and quipazine produced between 0 and 35% responding on the D-16949 lever. 8-Hydroxy-2-(di-n-propylamino)-tetralin substituted partially (45%) for D-16949, whereas 1-(m-trifluoromethylphenyl)-piperazine and RU 24969 completely and dose-dependently substituted for D-16949. The discriminative stimulus effects of D-16949 were not reversed by either cyproheptadine, ketanserin, pirenperone, spiperone or methylsergide. The 5-hydroxytryptamine3 (5-HT3) active antagonists ICS 205-930 and MDL 72222 were also ineffective as D-16949 antagonists. It is concluded that the discriminative stimulus effects of D-16949 are not mediated through opioid or 5-HT2 mechanisms. The present data also do not suggest the involvement of 5-HT3 mechanisms, but that D-16949 produces its discriminative stimulus effects in the rat primarily via agonistic actions at 5-HT1B receptors.

Tramadol reference source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1335050&dopt=Abstract tramadol Ultram

unimi.it

Tramadol quantitative determination by gas chromatography-mass spectrometry (GC/MS) using nefopam hydrochloride as internal standard (IS) and two calibration curves because of the large range of concentration attended in the plasmatic samples is described. Plasma samples drawn from subjects in postoperative period treated with two different initial intravenous (iv) bolus of tramadol (50 and 100 mg) followed by tramadol at the same infusion rate (12 mg h(-1)) are analysed. We operated for the qualitative analysis in Scan mode while for the quantitative analysis in SIM mode, selecting the ion m/z 58 for tramadol and m/z 179 for IS. The limit of detection (LOD) was 0.01 microg ml(-1) and the limit of quantification was 0.04 microg ml(-1).

Tramadol reference source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=13679190&dopt=Abstract tramadol Ultram [PubMed - in process]




Clin Investig. 1992 Aug;70(8):708-10.
The metabolism of tramadol by human liver microsomes.

Paar WD, Frankus P, Dengler HJ.

Zentrum fur Innere Medizin-Allgemeine Innere Medizin, Universitat Bonn.

The metabolism of tramadol was investigated in vitro using microsomal fractions of human liver. The parent compound and its main metabolites were determined by a newly developed high performance liquid chromatography assay. O-demethylation of tramadol was found to be stereoselective. The Vmax of the O-demethylation of (-)-tramadol was 210 pmol.mg-1.min-1, whereas (+)-tramadol was O-demethylated with a Vmax of 125 pmol.mg-1.min-1. The Km for both enantiomers was determined to be 210 microM. O-demethylation was inhibited competitively by quinidine (ki = 15 nM) and propafenone (ki = 34 nM). N-demethylation was also stereoselective, preferentially metabolizing the (+)-enantiomer. Whereas O-demethylation displayed monophasic Michaelis-Menten kinetics, N-demethylation was best described by a two-site model. Competitive inhibition of the O-demethylation both by quinidine and propafenone suggests that O-demethylation is carried out by P-450IID6.

Tramadol reference source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1392452&dopt=Abstract tramadol Ultram




Anaesthesist. 1992 Oct;41(10):634-8.
[Continuous peridural anesthesia in abdominal surgery. An alternative for elderly patients]

[Article in German]

Fuchs C.

Kreiskrankenhaus Bad Salzungen, Klinik fur Anaesthesie und Intensivtherapie, Bad Liebenstein.

Being advanced in years is not in itself a high risk in anaesthesia; however, altered pharmacokinetics and pharmacodynamics, mental dysfunction and the administration of anaesthetics complicate the postoperative period. In order to examine the problem of sedation in elderly patients, we studied the effects and side effects of continuous peridural anaesthesia for abdominal surgery. METHODS. On the day before surgery we inserted a peridural catheter (Perifix 400, Braun, Melsungen, FRG) between T-12 and L-4 in 52 patients in a sitting position (mean age 69.3 +/- 10.9 years) using the loss-of-resistance technique. If no signs of spinal anaesthesia became apparent, the exact position of the catheter was determined using 9 or 10 ml bupivacaine 0.5%. Next day, after premedication with atropine, pethidine or midazolam, 20-25 ml bupivacaine 0.5% was instilled through the peridural catheter. During surgery patients were sedated using a small dose of propofol. We also insufflated oxygen (2 l/min). Blood pressure, heart rate, and blood gases were monitored and electrocardiography and pulse oximetry performed. As postoperative pain therapy, we administered morphine through the peridural catheter at intervals of 8 h. For statistical evaluation we used Wilcoxon's test. RESULTS. An adequate degree of analgesia was found between T-4 and T-7 and abdominal muscle relaxation was satisfactory. Heart rate decreased by 10.3% after the administration of local anaesthetics. After surgery had begun, blood pressure decreased over a period of 30 min (systolic by 20.5% and diastolic by 14.2%) but it remained constant at this level during the rest of the operation (see Fig. 1). Neither of these side effects was significant. Oxygen saturation and blood gases were normal. During the operation, a mean dose of 325 mg propofol/h was necessary to maintain sedation. After surgery all patients were awake, suffered no pain and had complete amnesia with regard to the operation. The postoperative peridural dosage of 5 mg morphine (three times in 24 h) was very effective. Because some patients vomited we used between 50 and 100 mg tramadol (four times in 24 h) instead of morphine. Early mobilization of patients was possible and there were no pulmonary complications such as pneumonia. CONCLUSIONS. If carried out by an experienced physician, continuous peridural anaesthesia can be an alternative method in abdominal surgery for elderly patients. We see advantages in the minimal disturbance of pulmonary and mental function, in the minimal amount of sedation required and in the successful postoperative pain therapy.

Tramadol reference source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1443512&dopt=Abstract tramadol Ultram

ukb.uni-bonn.de

Genetic polymorphisms result in absent enzyme activity of CYP2D6 (poor metabolizers, PM) in about 10% of the Caucasian population. This study investigates whether the PM genotype has an impact on the response to tramadol analgesia in postoperative patients. A prospective study design was used and 300 patients recovering from abdominal surgery were enrolled. After titration of an individual loading dose, patients could self-administer 1 ml bolus doses of the drug combination tramadol 20 mg/ml, dipyrone 200 mg/ml and metoclopramide 0.4 mg/ml via patient-controlled analgesia (PCA). Patients' genotype was analyzed considering the most prevalent PM associated CYP2D6 mutations using a real-time PCR and hybridization based genotyping method. Demographic data, surgery related variables, pain scores, analgesic consumption and need for rescue medication were compared between extensive metabolizers (EM) and PM. The primary outcome criterion 'response' was defined as responder or non-responder status by the need for rescue medication and patients' satisfaction at the final interview. Demographic and surgery related data were comparable between EM (n=241) and PM (n=30). The percentage of non-responders was significantly higher in the PM group (46.7%) compared with the EM group (21.6%; p=0.005). Tramadol loading dose amounted to 108.2+/-56.9 and 144.7+/-22.6 mg (p<0.001) in EM and PM, respectively. More patients displaying the PM genotype needed rescue medication in the recovery room and during PCA period than patients with at least one wild type allele (21.6 versus 43.3%, p=0.02). PM for CYP2D6 showed a lower response rate to postoperative tramadol analgesia than EM. Therefore, CYP2D6 genotype has an impact on analgesia with tramadol. Pharmacogenetics may explain some of the varying response to pain medication in postoperative patients.

Tramadol reference source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14499440&dopt=Abstract tramadol Ultram