Can any of the following drugs cause seizures: sertraline, zopiclone, tramadol or paracetamol?/nA 3

Fråga: Can any of the following drugs cause seizures: sertraline, zopiclone, tramadol or paracetamol? A 30-year-old man is being treated with tramadol 100-400 mg, sertraline 75 mg and carbamazepine 600 mg daily, as well as zopiclone 5 mg and paracetamol 1.0 g as needed. Seizures occurred after the start of tramadol treatment (for back pain after a fracture) a couple of years ago. Sertraline treatment was started this summer.

Sammanfattning: Tramadol and sertraline can both cause seizures, in monotherapy and at therapeutic doses. The risk of seizures is increased when the two drugs are combined.

Svar: Tramadol is known to cause seizures, although not frequently, as discussed in an earlier Drugline document (1). Concomitant treatment with antidepressants, such as sertraline, seems to increase that risk. The combination of tramadol and sertraline has also been reported to cause serotonergic syndrome in rare cases. This can be due to the fact that one of the enantiomers of the racemic drug tramadol also acts as a serotonin reuptake inhibitor (2).

Sertraline, as well as other antidepressants, can lower the seizure threshold, and also be the cause of seizures, predominantly in predisposed patients. This effect is dose-related, and also drug-related. Sertraline is believed to have rather a low potential to induce seizures, as compared with for example clomipramine (3).

For zopiclone, seizures have been reported as a withdrawal phenomenon, indicating that this substance, like benzodiazepines, may have some anti-convulsive properties (4).

Paracetamol is not known to cause seizures.

Sertraline, zopiclone, tramadol and carbamazepine are all to some extent metabolised by the same enzyme, CYP3A4. Competition for the binding sites to this enzyme may cause inhibition of the metabolism of any of the drugs. On the other hand, carbamazepine is known to induce (increase) the activity of CYP3A4, which may lead to sub therapeutic concentrations of the other drugs. It is not possible to say what will be the net effect in the present patient.

As seizures occurred after the start of tramadol treatment, it is strongly recommended that this treatment be stopped. An alternative analgesic could be a combination of paracetamol and codeine. (Opiates are not pro-convulsive). Paracetamol should given in a high enough dose, as carbamazepine does also increase the glucuronidation of paracetamol. Hopefully, carbamazepine treatment can be slowly tapered. It should then be noted, that doses of especially sertraline may have to be decreased, as enzyme induction decreases. Otherwise, the possibly higher levels of sertraline may be the cause of seizures. Sertralin concentrations can be monitored in plasma.