Co-administration of quinidine, a potent CYP2D6 enzyme inhibitor, with tramadol, a combination which results in markedly reduced levels of desmetramadol, was found not to significantly affect the analgesic effects of tramadol in human volunteers. However, other studies have found that the analgesic effects of tramadol are significantly decreased or even absent in CYP2D6 poor metabolizers. The analgesic effects of tramadol are only partially reversed by naloxone in human volunteers, hence indicating that its opioid action is unlikely the sole factor; tramadol's analgesic effects are also partially reversed by α-adrenergic receptor antagonists such as yohimbine, the 5-HT receptor antagonist ondansetron, and the 5-HT receptor antagonists SB-269970 and SB-258719. Pharmacologically, tramadol is similar to tapentadol and methadone in that it not only binds to the MOR, but also inhibits the reuptake of serotonin and norepinephrine due to its action on the noradrenergic and serotonergic systems, such as its "atypical" opioid activity.
Tramadol has inhibitory actions on the 5-HT receptor. Antagonism of 5-HT could be partially responsible for tramadols reducing effect on depressive and obsessive–compulsive symptoms in patients with pain and co-morbid neurological illnesses. 5-HT blockade may also account for its lowering of the seizure threshold, as 5-HT knockout mice display significantly increased vulnerability to epileptic seizures, sometimes resulting in spontaneous death. However, the reduction of seizure threshold could be attributed to tramadols putative inhibition of GABA receptors at high doses (significant inhibition at 100 μM). In addition, desmetramadol is a high-affinity ligand of the DOR, and activation of this receptor could be involved in tramadol's ability to provoke seizures in some individuals, as DOR agonists are well known for inducing seizures.
Nausea and vomiting caused by tramadol are thought to be due to activation of the 5-HT receptor via increased serotonin levels. In accordance, the 5-HT receptor antagonist ondansetron can be used to treat tramadol-associated nausea and vomiting. Tramadol and desmetramadol themselves do not bind to the 5-HT receptor.