[The opioid tramadol demonstrates excitatory properties of non-opioid character--a preclinical study using alfentanil as a comparison]

[Article in German]

Neruda B.

Abteilung fur Gefasschirurgie und Nierentransplantation, Operatives Zentrum, Heinrich-Heine-Universitat Dusseldorf.

Tramadol, an analgesic with mean potency one tenth that of morphine is used regularly for the treatment of chronic and postoperative pain. Previous reports have indicated that tramadol may induce seizure activity when given together with a selective serotonin reuptake inhibitor (SSRI). Therefore, its major mode of action may be questioned which purportedly is due to binding with the opioid receptor and partly due to the inhibition of monoamine reuptake.We therefore set out to study its potential in inducing seizure activity and to quantify its effect on EEG-power spectra and on the central modulation of sensory afferents in awake and trained dogs (n=7). In order to demonstrate if opioid receptors mediated these effects, incremental doses of tramadol were given which was followed by naloxone for possible reversal. After a wash-out period the same animals were exposed to graded doses of alfentanil, a pure mu-receptor agonist. Again this was followed by the opioid antagonist naloxone for reversal.The electroencephalogram (EEG) and the event-related evoked potentials (SEP) were used to demonstrate possible excitatory effects. In order to derive the SEP the front paw was stimulated electrically (Digi Stim II trade mark ) while the evoked potentials were picked up contralaterally from the somatosensory cortex using stick-on electrodes. 256 sweeps were averaged (Lifescan) and the peak-to-peak amplitude was measured to demonstrate CNS excitation compared to control (%). Additionally, the raw electroencephalogram was viewed for epileptogenic changes and its power computed into the various power bands alpha, beta, delta und theta using FFT over a time epoch of 60 s. Following control, graded doses of either tramadol (2-5-10 mg/kg i.v.) or alfentanil (10-30-60 microg/kg i.v.) were given every 15 min while the EEG and the SEP were recorded. Thereafter naloxone (20 microg/kg i.v.) was injected for reversal.Tramadol did not suppress the amplitude of the SEP at any dose. High doses (>5 mg/kg i.v.) resulted in an increase (+100%) of the amplitude of the evoked potential. This was accompanied by short-term muscle fibrillations, and a short-term spike-and-wave activity in the EEG followed by a long-lasting theta-dominance. These effects could not be reversed by naloxone. In contrast to tramadol, alfentanil induced a dose-related depression of amplitude in the SEP with a maximum of 82% suggesting a depressive effect of modulation of afferents in the sensory cortex. This effect was fully naloxone reversible and was followed by a rebound in amplitude of the SEP together with an increase in fast beta-waves in the EEG.Tramadol very little mediates its central action via the mu-opioid receptor as the present effects were not naloxone reversible. Consistent with the results is the very low affinity of tramadol to the opioid receptor which is several thousand times less than that of morphine. Most likely, inhibition of central norepinephrine and serotonin reuptake as well as the reduction in 5-HT-turnover may contribute to the effects of tramadol. Due to the monoamine reuptake inhibition an increase in transmission may result, triggering off excitatory phenomena with spike-and-wave activity in the CNS. Such excitatory effects, however, may only be seen when tramadol is used in doses exceeding the therapeutic range.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12799988&dopt=Abstract tramadol



Actions of tramadol on micturition in awake, freely moving rats.

Andersson KE.

Department of Clinical Pharmacology, Lund University Hospital, Lund, Sweden. Grunenthal GmbH, Aachen, Germany.

1 (+/-)-Tramadol, a widely used analgesic, is a racemate stimulating opioid receptors and inhibiting reuptake of noradrenaline and serotonin, that is, pharmacological principles previously shown to influence rat micturition. 2 We studied both (+/-)-tramadol and its enantiomers in conscious Sprague-Dawley rats undergoing continuous cystometry. The effects of these agents were compared to those of morphine ( micro -opioid receptor agonist) and tested after pretreatment with naloxone ( micro -opioid receptor antagonist). Cystometries were evaluated before and after intravenous (i.v.), intraperitoneal (i.p.) and intrathecal (i.t.) drug administrations. 3 The most conspicuous effects of i.v. (+/-)-tramadol (0.1-10 mg kg(-1)) was an increase in threshold pressure and an increase in micturition volume. 4 These effects were mimicked by (+)-tramadol (0.1-5 mg kg(-1) i.v.), whereas (-)-tramadol (5 mg kg(-1) i.v.) did not influence threshold pressure and micturition volume. 5 The effects of (+/-)-tramadol 5 mg kg(-1) on micturition volume were blocked by pretreatment with naloxone 0.3 mg kg(-1). Morphine (0.3-10 mg kg(-1) i.p.) increased threshold pressure but did not significantly increase micturition volume in doses not resulting in overflow incontinence. 6 (+/-)-Tramadol 10 mg kg(-1) increased urine production, an effect blocked by desmopressin 25 ng kg(-1). 7 (+/-)-Tramadol effectively inhibits micturition in conscious rats by stimulating micro -opioid receptors. A synergy between opioid receptor stimulation and monoamine reuptake inhibition may contribute to the micturition effects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12812997&dopt=Abstract tramadol



The antinociceptive effect of tramadol-venlafaxine combination on the paw withdrawal threshold in a rat model of neuropathic pain.

Soykan N.

Pain Clinic, Department of Anesthesiology, Bornova, Izmir, Turkey. meltem med.ege.edu.tr

The combination of venlafaxine and tramadol was compared with the single use of these agents to investigate the antinociceptive effect on paw withdrawal latency (PWL) to paw pressure in rats with neuropathic pain. Rats were divided into 4 groups: group 1 received saline (0.2 ml i.p.); group 2 received venlafaxine (22 mg/kg i.p.); group 3 received tramadol (20 mg/kg i.p.); and group 4 received venlafaxine + tramadol. No statistically significant changes were observed in the saline and venlafaxine groups with respect to PWL in the lesioned paw. However, tramadol produced a significant antinociceptive effect on the lesioned paw at 30 min compared with the saline and venlafaxine groups. A more potent antinociceptive effect was observed in the tramadol + venlafaxine group, beginning at 60 min and lasting for 1 h. The combination of venlafaxine + tramadol was more effective in increasing the pain threshold in this animal model of neuropathic pain than either of these drugs administered alone. (c) 2003 Prous Science. All rights reserved.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12851658&dopt=Abstract tramadol



Post-mortem SNP analysis of CYP2D6 gene reveals correlation between genotype and opioid drug (tramadol) metabolite ratios in blood.

Sajantila A.

Laboratory of Forensic Biology, Department of Forensic Medicine, P.O. Box 40, 00014, University of Helsinki, Finland.

Tramadol is an opioid drug metabolised in phase I by cytochrome P450 (CYP) enzymes, of which CYP2D6 is mainly responsible for the O-demethylation of tramadol, but is not involved in N-demethylation. Defects in the genes encoding drug metabolising enzymes (DMEs) may lead to adverse drug effects, even to death. To aid interpretation of the forensic toxicology results, we studied how the genetic variation of the CYP2D6 gene is reflected in tramadol metabolite ratios found in post-mortem samples. In 33 Finnish autopsy cases where tramadol was found, we analysed both the CYP2D6 genotype and the concentrations of tramadol and its metabolites O- and N-demethyltramadol. As expected, we found a correlation between the number of functional CYP2D6 alleles and the ratio of tramadol to O-demethyltramadol. We also found a correlation between the number of functional alleles and the ratio of tramadol to N-demethyltramadol. This can be explained by the complementary nature of the two main tramadol demethylation pathways. No known CYP2D6 inhibitors were associated with exceptional metabolic ratios. Furthermore, no accidental tramadol poisonings were associated with a defective CYP2D6 gene. Our results on the tramadol are among the first to demonstrate that genetic variation in drug metabolising enzymes can be analysed in post-mortem blood, and that it correlates well with the parent drug to metabolite ratios. The results also suggest that genetic factors play, in general, a dominant role over other factors in the metabolism of individual drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12893130&dopt=Abstract tramadol