Can Nobligan (tramadol) have an antidepressive effect? Can tramadol potentiate the effect of SSRIs?

Fråga: Can Nobligan (tramadol) have an antidepressive effect? Can tramadol potentiate the effect of SSRIs?

Tramadol is sometimes used in combination with citalopram in geriatric patients.

Sammanfattning: We couldn´t find any report about a clear antidepressive effect of tramadol. Due to some similarities in the mechanism of action between tramadol and SSRIs and some reports about possible pharmacodynamic and/or pharmacokinetic interactions between these drugs, we suggest caution when adding tramadol in therapy to the patients treated with SSRIs. Such patients need a careful follow-up.

Svar: Tramadol is a centrally acting analgesic with a dual mechanism of action within the CNS: it exerts agonistic properties at opiate receptors and interferes with neurotransmitters reuptake (1). The perception of pain involves one descending inhibitory pathway from the midbrain that releases serotonin and another descending pathway in the pons that releases norepinephrine (2). Tramadol is effective on the pain inhibiting the reuptake of the natural neurotransmitter norepinephrine and stimulating the release of serotonin (1). The similarity in mechanism of action of tramadol and tricyclic antidepressant agents suggests the possibility that the drug may be effective in neuropathic pain conditions with central hyperexcitability, for which tricyclics are mainly used (1). Tramadol also binds weakly to mu-opiate receptors, blocking the transmission of pain signals to the brain. Tramadol, administered orally, is rapidly absorbed and shows a bioavailability roughly around 75 per cent. The drug is extensively metabolised in the liver via two metabolic pathways to form N- and O-demethylated tramadol. The production of O-demethyl tramadol, the only active metabolite, which shows analgesic activity greater than that of the parent compound, since its affinity with the mu-receptors is greater than the tramadol one, seems to depend on the polymorphic isozyme of the P-450 cytochrome, CYP2D6 (1).

Many studies (3,4) suggest that compounds with SSRI activity are likely to interact with this isozyme in vivo with the potential of causing drug interactions. In in vitro receptor binding and synaptosomal experiments (5) it has been seen that there are some similarities in the influence on the 5-HT turnover between the SSRI fluoxetine and tramadol.

In the international literature it has been possible to find out some reports concerning a possible pharmacodynamic interaction between tramadol and SSRIs. Two of these reports were concerning the appearance of a serotonin syndrome. In the first case (6), concerning a 47-year-old man who developed serotonin syndrome after being prescribed a combination of paroxetine and tramadol, the time relationship and the absence of other medications or factors was suggestive of a causal relationship between the coadministration of the two drugs and the occurrence of the syndrome.

The second case (7) was concerning a 42-year-old woman who developed serotonin syndrome when she was taking multiple medications, including tramadol and sertraline. In this case the inhibition of CYP2D6 by sertraline was suspected to be an important factor in the interaction.

In another report (8), concerning the appearance of galactorrhea in a 34-year-old woman in therapy with citalopram, tramadol and alprazolam, the temporal relationship between the drugs co-administrations and the side effect appearance as well as the drugs potential similar effects on prolactin concentrations suggest a pharmacodynamic interaction between these three drugs.

In one more case (9), concerning a 41-year-old man dead presumably because a fatal serotonin syndrome developed as a result of a multiple drug intoxication (the drugs mainly suspected being moclobemide and clomipramine), tramadol was suspected to have a synergistic effect on the serotonin syndrome.

Finally, we found a report (10) concerning the appearance of nightmares and hallucinations after long term intake of tramadol combined with antidepressants (in this case paroxetine and dosulepine). This suggests to us the opportunity to focus on the need that the chronic use of pain killing drugs, especially in combination with psychoactive drugs, should be limited in time whenever possible, especially if the pain completely disappears or when the pain aetiology or diagnosis is not clear. 1 Poulsen L, Arendt-Nielsen L. Brosen K, Sindrup SH: The hypoalgesic effect of tramadol in relation to CYP2D6. Clin Pharmacol Ther 1996; 60: 636-644 2 Lee CR, McTavish D, Sorkin EM: Tramadol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs 1993; 46: 313-340 3 Crewe HK, Lennard MS, Tucker GT, Woods FR, Haddock RE: The effect of selective serotonin re-uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes. Br J Clin Pharmacol 1992; 34: 262-265 4 Harvey AT, Preskorn SH: Cytochrome P450 enzymes: interpretation of their interactions with selective serotonin reuptake inhibitors. Part I. J Clin Psychopharmacol 1996; 16: 273-355 5 Frink MC, Hennies H-H, Englberger W, Haurand M, Wilffert B: Influence of tramadol on neurotransmitter systems of the rat brain. Arzneimittelforschung 1996; 46: 1029-1036 6 Egberts ACG, Borgh J ter, Brodie-Meijer CCE: Serotonin syndrome attributed to tramadol addition to paroxetine therapy. Int Clin Psychopharmacol 1997; 12: 181-182 7 Mason BJ, Blackburn KH: Possible serotonin syndrome associated with tramadol and sertraline coadministration. Ann Pharmacother 1997; 31: 175-177 8 Bondolfi G, Rubin C; Bryois C, Eap CB: Galactorrhoea induced by a pharmacodynamic interaction between citalopram, alprazolam and tramadol: a case report. Therapie 1997; 52: 76-77 9 Hernandez AF, Montero MN, Pla A, Villanueva E: Fatal moclobemide overdose or death caused by serotonin syndrome? J Forensic Sci 1995; 40: 128-130 10 Devulder J, De Laat M, Dumoulin K, Renson A, Rolly G: Nightmares and hallucinations after long term intake of tramadol combined with antidepressants. Acta Clinica Belgica 1996; 51: 184-186