Tramadol Drug Interactions

Tramadol Drug Interactions

Tramadol is used in clinical practice, but it does have numerous drug interactions that you should be aware of. When reviewing a medication list or when a patient starts a new medication, here are some of the items that I think about when monitoring for tramadol drug interactions.

Seizure Risk

Antiepileptic agents are always something I look for in a medication list when tramadol is prescribed. Tramadol can lower the seizure threshold and increase the risk of seizures. When you see a patient on phenytoin, levetiracetam, or other seizure medications, it should prompt you to address the risk versus benefit of continuing tramadol for pain management.

CYP2D6 Alterations

When assessing tramadol drug interactions, you must remember that tramadol’s primary analgesic effect is due to conversion to an active metabolite. CYP2D6 is responsible for this conversion. When CYP2D6 is inhibited, it may lead to higher concentrations of tramadol and lower concentrations of the active metabolite which carries the primary analgesic effect.

Additive Sedation

With tramadol’s opioid activity, we must be careful with other agents that can add to sedation. Benzodiazepines, gabapentin, pregabalin, Z-drugs, alcohol, and anticholinergics are classic examples of medications that can have additive sedation.


In addition to the sedative type properties of tramadol, constipation is a very real adverse effect for some patients. Be aware of other medications that may contribute to constipation such as anticholinergics and calcium channel blockers.

Serotonin Syndrome

In addition to its opioid activity, tramadol can inhibit the reuptake of serotonin and norepinephrine. Because of this mechanism, we can certainly have additive effects on serotonin. SSRIs, SNRIs, TCAs, MAOIs, and linezolid are a few examples of medications that can increase the risk of serotonin syndrome when used in combination with tramadol.

Serotonin syndrome is extremely rare, and I tend to have more concern for it as doses increase or as the number of medications with serotonin activity increases.

There is my main list of tramadol drug interactions. What else would you add to this list?

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Written By Eric Christianson

January 17, 2021

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