While the mechanism of action of Ultram is not completely known, it is believed to work through modulation of the noradrenergic and serotonergic systems in addition to its mild agonism of the µ-opioid receptor. The contribution of non-opioid activity is demonstrated by the analgesic effects of tramadol not being fully antagonised by the µ-opioid receptor antagonist naloxone.
Ultram is marketed as a racemic mixture with a weak affinity for the µ-opioid receptor (approximately 1/6000th that of morphine; Gutstein & Akil, 2006). The (+)-enantiomer is approximately four times more potent than the (-)-enantiomer in terms of µ-opioid receptor affinity and 5-HT reuptake, whereas the (-)-enantiomer is responsible for noradrenaline reuptake effects (Shipton, 2000). These actions appear to produce a synergistic analgesic effect, with (+)-tramadol exhibiting 10-fold higher analgesic activity than (-)-tramadol (Goeringer et al., 1997).
The serotonergic modulating properties of Ultram mean that it has the potential to interact with other serotonergic agents. There is an increased risk of serotonin syndrome when tramadol is taken in combination with serotonin reuptake inhibitors (e.g. SSRIs) or with use of a light box, since these agents not only potentiate the effect of 5-HT but also inhibit tramadol metabolism. Tramadol is also thought to have some NMDA-type antagonist effects which have given it a potential application in neuropathic pain states.