THE PHARMACOLOGY OF TRAMADOL

(+/-)-Tramadol is a synthetic 4-phenyl-piperidine analogue of codeine. It is a central analgesic with a low affinity for opioid receptors, I ts selectivity for mu receptors has recently been demonstrated, asci t he M1 metabolite of tramadol, produced by liver O-demethylation, shows a higher affinity for opioid receptors than the parent drug, The rate of production of this M1 derivative (O-demethyl tramadol), is influen ced by a polymorphic isoenzyme df the debrisoquine-type, cytochrome P4 50 2D6 (CYP2D6), Nevertheless, this affinity for mu receptors of the C NS remains low. being 6000 times lower than that of morphine, Moreover , and in contrast to other opioids, the analgesic action of tramadol i s only partially inhibited by the opioid antagonist naloxone, which su ggests the existence of another mechanism of action. This was demonstr ated by the discovery of a monoaminergic activity thar inhibits noradr enaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) reu ptake, making a significant contribution to the analgesic action by bl ocking nociceprive impulses at the spinal level, (+/-)-Tramadol is a r acemic mixture of 2 enantiomers, each one displaying differing affinit ies for various receptors. (+)-Tramadol is a selective agonist or mu r eceptors and preferentially inhibits serotonin reuptake, whereas (-)-t ramadol mainly inhibits noradrenaline reuptake. The action of these 2 enantiomers is both complementary and synergistic and results in the a nalgesic effect of (+/-)-tramadol After oral administration, tramadol demonstrates 68% bioavailability, with peak serum concentrations reach ed within 2 hours. The elimination kinetics can be described as 2-comp artmental, with a half-life of 5.1 hours for tramadol and 9 hours for the M1 derivative after a single oral dose of 100mg. This explains the approximately 2-fold accumulation of the parent drug and its M1 deriv ative that is observed during multiple dose treatment with tramadol. T he recommended daily dose of tramadol is between 50 and 100mg every 4 to 6 hours, with a maximum dose of 400 mg/day; the duration of the ana lgesic effect after a single oral dose of tramadol 100mg is about 6 ho urs. Adverse effects, and nausea in particular, are dose-dependent and therefore considerably more likely to appear if the loading dose is h igh-The reduction of this dose during the first days of treatment is a n important factor in improving tolerability. Other adverse effects ar e generally similar to those of opioids, although they are usually les s severe, and can include respiratory depression, dysphoria and consti pation. Tramadol can be administered concomitantly with other analgesi cs, particularly those with peripheral action, while drugs that depres s CNS function may enhance the sedative effect of tramadol. Tramadol s hould not be administered to patients receiving monoamine oxidase inhi bitors, and administration with tricyclic antidepressant drugs should also be avoided. Tramadol has pharmacodynamic and pharmacokinetic prop erties that are highly unlikely to lead to dependence. This was confir med by various controlled studies and postmarketing surveillance studi es, which reported an extremely small number of patients developing to lerance or instances of tramadol abuse. Tramadol is a central acting a nalgesic which has been shown to be effective and well tolerated, and likely to be of value for treating several pain conditions (step II of the World Health Organization ladder) where treatment with strong opi oids is not required.