To the Editor: There have been a number of reports that combination therapy with tramadol and the selective serotonin reuptake inhibitors (SSRIs) fluoxetine (1), paroxetine (2), and sertraline (3) can lead to serotonin syndrome. Citalopram monotherapy has also been described as leading to serotonin syndrome (4), but we believe this has not yet been observed under coadministration with tramadol.
Ms. A was a 70-year-old Caucasian woman with a 30-year history of mild recurrent depressive disorder whose illness had been in remission for 3 years while she was taking 10 mg/day of citalopram. Three days after an abdominal operation, she began taking 50 mg/day of tramadol for pain relief, but she subsequently developed tremors, restlessness, fever, confusion, and visual hallucinations. Her symptoms stopped after termination of tramadol therapy. One year later, she developed identical symptoms upon taking 20 mg/day of tramadol after an abdominal hernia operation. Ms. A had been taking citalopram without interruption.
To assess Ms. A’s drug metabolizing activity, we genotyped her for the functional polymorphisms in cytochrome P450 enzymes CYP2D6 and CYP2C19, revealing her to be heterozygous for alleles causing deficient activity in both enzymes (CYP2D6*1/*4 and CYP2C19*1/*2). Her racemic citalopram clearance was 3.0 ml/kg/min, which is lower than the usual mean of 5.5 ml/kg/min (SD=1.7) (5).
Under combination therapy with citalopram and tramadol, Ms. A showed symptoms typical of serotonin syndrome. Re-exposure to the same drug combination resulted in the same symptoms, leading us to the conclusion that we were indeed dealing with drug-induced serotonin syndrome.
Citalopram is metabolized by CYP2C19, whereas tramadol is O-methylated by CYP2D6(6). The patient was a heterozygous carrier of deficient alleles for both enzymes. Thus, the metabolizing capacity of both pathways was reduced. Furthermore, SSRIs are known to have an inhibitory effect on CYP2D6(7). A decrease in the elimination of citalopram might strengthen this effect, leading to a further reduction in tramadol metabolism. Our patient may exemplify the clinical importance of combined heterozygous genotypes of CYP2D6 and CYP2C19, which occurs in approximately 30% of Caucasians (8).