Tramadol can have pharmacodynamic, pharmacokinetic, and pharmacogenetic interactions.
Tramadol is metabolized by CYP2D6 enzymes which contribute to the metabolism of approximately 25% of all medications. Any medications with the ability to inhibit or induce these enzymes may interact with tramadol. These include common antiarrhythmics, antiemetics, antidepressants (sertraline, paroxetine, and fluoxetine in particular), antipsychotics, analgesics, and tamoxifen.
Due to tramadols serotonergic effects, tramadol has the potential to contribute to the development of an acute or chronic hyper-serotonin state called serotonin syndrome when used concurrently with other pro-serotonergic medications such as antidepressants (SSRIs, SNRIs, tricyclics, MAOIs), antipsychotics, triptans, cold medications containing dextromethorphan, and some herbal products such as St. Johns wort.
Concurrent use of 5-HT3 antagonists such as ondansetron, dolasetron, and palonosetron may reduce the effectiveness of both drugs.
Tramadol also acts as an opioid agonist and thus can increase the risk for side effects when used with other opioid and opioid-containing analgesics (such as morphine, pethidine, tapentadol, oxycodone, fentanyl, and Tylenol 3).
Tramadol increases the risk for seizures by lowering the seizure threshold. Using other medications that lower seizure threshold - such as antipsychotic medications, bupropion (an anti-depressant and smoking cessation drug), and amphetamines - can further increases this risk.