Should Tradolan (tramadol) treatment be considered contraindicated in a patient treated with Remero

Fråga: Should Tradolan (tramadol) treatment be considered contraindicated in a patient treated with Remeron (mirtazapine)?

Sammanfattning: Theoretically, while it is possible that pharmacokinetic or pharmacodynamic interactions can occur between mirtazapine and tramadol, there is no clinical evidence that these occur in practice. As usual, whenever a previously untried combination treatment is initiated, attention should be given towards unexpected effects, here eg developing serotonin syndrome or seizures. If the patient is treated with both drugs, therapeutic drug monitoring of mirtazapine can be carried out to rule out, or handle a pharmacokinetic interaction.

Svar: No clinical reports concerning drug interactions between mirtazapine and tramadol were found in available literature. Theoretically, pharmacokinetic and pharmacodynamic interactions between tramadol and mirtazapine can occur. Tramadol is a centrally acting analgesic with both monoaminergic and opiod mechanism of actions (1,2). It inhibits neurotransmitter reuptake (noradrenalin and serotonin) and is an agonist on my-opiod receptors. Mirtazapine is an antidepressant, which is a presynaptic alpha2antagonist and thereby enhances noradrenergic neurotransmission (2). The effect of both tramadol and mirtazapine on the monoamine, especially serotonin, levels suggest the possibility of a pharmacodynamic interaction. Further, it is theoretically possible that mirtazapine and tramadol can interact pharmacokinetically since both drugs are partly metabolised by the same cytochrome P450 isoenzymes, CYP3A4 and CYP2D6 (2,3). In addition, in vitro studies have shown that mirtazapine can be a competitive inhibitor of the same enzymes (3). Mirtazapine is though a much weaker inhibitor than fluoxetine for CYP2D6 and ketokonazole for CYP3A4 and this effect is not suspected to be of clinical relevance (3).

A few cases of serotonergic syndrome have been observed when tramadol has been used concomitantly with selective serotonin uptake inhibitors (SSRI) (1,4-9). The mechanism proposed to explain this interaction is additive serotonin reuptake inhibition resulting in increased serotonergic transmission. However, it is unknown how frequently this occurs in patients on this combination or whether it can be expected in patients on tramadol and mirtazapine treatment.

Tramadol and mirtazapine have both separately been reported as inducing seizures as rare side effect, in particular when predisposing factors exist (2,10). There are 4 respectively 14 cases of seizures possible related to mirtazapine and tramadol use reported to the Swedish Adverse Drug Reactions Advisory Committee (SADRAC) (11).