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However, other studies have found that the analgesic effects of tramadol are significantly decreased or even absent in CYP2D6 poor metabolizers.[11][67] The analgesic effects of tramadol are only partially reversed by naloxone in human volunteers,[11] hence indicating that its opioid action is unlikely the sole factor; tramadol’s analgesic effects are also partially reversed by α2-adrenergic receptor antagonists like yohimbine, the 5-HT3 receptor antagonist ondansetron, and the 5-HT7 receptor antagonists SB-269970 and SB-258719.[13][83] 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[3] due to its action on the noradrenergic and serotonergic systems, such as its “atypical” opioid activity.[84]
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