Tramadol is an opioid used to treat moderate to moderately severe pain. There are many good reasons to not prescribe tramadol, owning to its pharmacokinetic profile.

Tramadol is metabolized by CYP2D6 in the liver. The issue with CYP2D6 is it has the greatest amount of polymorphisms of all the CYPs enzymes (thus has the greatest potential variability in activity between patients). Additionally, CYP2D6 expression can vary from being non-functional (i.e. - non-metabolizer) to ultra-rapid metabolizer (this is due to its ability to be duplicated – no other CYP enzyme does this!).[1]

Tramadol (the parent drug) has both serotonergic/noradrenergic and weak opioid activity, while its M1 metabolite (after CYP2D6 metabolism) has much stronger opioid activity. Thus, main problem with tramadol is if a patient has a polymorphism of CYP2D6 that confers no activity (i.e. - does not metabolize tramadol), you essentially get an antidepressant effect from its serotonergic and noradrenergic effects. If, on the other hand, the patient is an ultrarapid metabolizer with duplicate copies of the gene, then the patient goes in the opposite direction and you run the risk of overdosing the patient on opiates. The only way to know this is to do pharmacogenetics testing, which is not often done. When prescribing tramadol, you either run the risk of prescribing an antidepressant (when you didn't intend to), or prescribing an excessive amount of opioids (which risks giving the patient an overdose!).