[The opioid tramadol demonstrates excitatory properties of non-opioid character--a preclinical study using alfentanil as a comparison].
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.
Freye
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E
Abteilung für Gefässchirurgie und Nierentransplantation, Operatives Zentrum, Heinrich-Heine-Universität Düsseldorf.
Latasch
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L
Von Bredow
G
G
Neruda
B
B