Mechanism of Action for Tramadol

Tramadol acts as a μ-opioid receptor agonist, serotonin releasing agent, norepinephrine reuptake inhibitor, NMDA receptor antagonist, 5-HT2C receptor antagonist, (α7)5 nicotinic acetylcholine receptor antagonist, TRPV1 receptor agonist, and M1 and M3 muscarinic acetylcholine receptor antagonist.

The analgesic action of tramadol is not fully understood, but it is believed to work through modulation of serotonin and norepinephrine in addition to its relatively-weak μ-opioid receptor agonism. The contribution of non-opioid activity is demonstrated by the fact that the analgesic effect of tramadol is not fully antagonised by the μ-opioid receptor antagonist naloxone.

Tramadol is marketed as a racemic mixture of the (1R,2R)- and (1S,2S)-enantiomers with a weak affinity for the μ-opioid receptor (approximately 1/6000th that of morphine; Gutstein & Akil, 2006). The (1R,2R)-(+)-enantiomer is approximately four times more potent than the (1S,2S)-(–)-enantiomer in terms of μ-opioid receptor affinity and 5-HT reuptake, whereas the (1S,2S)-(–)-enantiomer is responsible for noradrenaline reuptake effects (Shipton, 2000). These actions appear to produce a synergistic analgesic effect, with (1R,2R)-(+)-tramadol exhibiting 10-fold higher analgesic activity than (1S,2S)-(–)-tramadol (Goeringer et al., 1997).

The serotonergic-modulating properties of tramadol give it the potential to interact with other serotonergic agents. There is an increased risk of serotonin toxicity when tramadol is taken in combination with serotonin reuptake inhibitors (e.g., SSRIs), since these agents not only potentiate the effect of 5-HT but also inhibit tramadol metabolism.[citation needed] Tramadol is also thought to have some NMDA antagonistic effects, which has given it a potential application in neuropathic pain states.

Tramadol has inhibitory actions on the 5-HT2C receptor. Antagonism of 5-HT2C could be partially responsible for tramadol's reducing effect on depressive and obsessive-compulsive symptoms in patients with pain and co-morbid neurological illnesses. 5-HT2C blockade may also account for its lowering of the seizure threshold, as 5-HT2C knockout mice display significantly increased vulnerability to epileptic seizures, sometimes resulting in spontaneous death. However, the reduction of seizure threshold could be attributed to tramadol's putative inhibition of GABA-A receptors at high doses.

The overall analgesic profile of tramadol supports use in the treatment of intermediate pain, especially chronic pain. It is slightly less effective for acute pain than hydrocodone, but more effective than codeine. It has a dosage ceiling similar to codeine, a risk of seizures when overdosed, and a relatively long half-life making its potential for misuse relatively low amongst intermediate strength analgesics.

Tramadol's primary active metabolite, O-desmethyltramadol, is a considerably more potent μ-opioid receptor agonist than tramadol itself. Thus, tramadol is in part a prodrug to O-desmethyltramadol. Similarly to tramadol, O-desmethyltramadol has also been shown to be a norepinephrine reuptake inhibitor, 5-HT2C receptor antagonist, and M1 and M3 muscarinic acetylcholine receptor antagonist.