Which antidepressants should be recommended to patients using tramadol?/nIn FASS (The Swedish catal

Fråga: Which antidepressants should be recommended to patients using tramadol? In FASS (The Swedish catalogue of approved medical products), a risk of interaction between tramadol and paroxetine, sertraline or fluoxetine is mentioned.

Sammanfattning: Combination treatment with tramadol and serotonin reuptake inhibitors increases the risk of serotonergic syndrome and seizures and should be avoided. Regarding the risk of seizures in predisposed individuals, no safe combination of tramadol and antidepressive agents can be recommended, and a change of analgesic treatment is to be preferred.

Svar: Tramadol has an inhibiting effect on synaptic noradrenalin and serotonin reuptake. Serotonergic syndrome has been reported when tramadol has been combined with the serotonin reuptake inhibitors (SSRIs) paroxetine, sertraline or fluoxetine. Furthermore, both SSRIs and tramadol decrease the seizure threshold, and therefore this combination should be avoided in patients with an increased risk of developing seizures (1).

In the files of the Swedish Adverse Reactions Advisory Committee (SADRAC) there are two cases, where seizures have appeared when tramadol have been used with sertraline or fluoxetine (2). In the literature, one lethal case has been reported, where a man with alcohol abuse died from seizures following treatment with tramadol, venlafaxin, trazodone and quetiapine, all of which have a potential to influence serotonin levels (3). There is also one case report describing a 72-year-old woman, who developed a serotonergic syndrome 18 days after treatment with tramadol (150 mg/day) and fluoxetine (20mg/day) was started (4). Serotonergic syndrome has also been reported in two cases of combination treatment with tramadol and paroxetine, and in one case with the combination of tramadol, olanzapine and mirtazapine (5, 6).

Tramadol is metabolised by the cytocrome P-450 enzymes CYP2D6 and CYP3A4. Paroxetine and fluoxetine are strong inhibitors, and sertraline is a weaker inhibitor, of CYP2D6. Therefore, metabolic interactions between these drugs are possible, but remain to be clinically proven (7, 8).

Generally, in patients who need antidepressant treatment, a change of analgesic treatment from tramadol to paracetamol is recommended. Paracetamol only, or in combination with a weak opioid might be used. In patients treated with fluoxetine or paroxetine, dextropropoxiphene is a better choice than codeine, as codeine is bio-activated to morphine via CYP2D6.

If the indication to use tramadol is strong, and the patient has no propensity for seizures, an antidepressant with less serotonergic effects, e.g. reboxetine, mianserin or maprotiline might be considered. A last alternative would be to combine a low dose of tramadol with a tricyclic antidepressant and use therapeutic drug monitoring to ensure lowest effective doses.