Antidepressant drugs have been used for many years to treat various pain syndromes. The mechanism of analgesic action is still unclear. The following factors most likely contribute to this effect: interfering with noradrenergic, serotoninergic, dopaminergic, GABA-ergic and opioid systems, adenosine reuptake inhibition, blocking of the NMDA receptor and ion channels. Analgesic action of tricyclic antidepressants (TcA) have been proven. In spite of their improved tolerance, selective serotonin reuptake inhibitors do not appear to be particularly effective in the treatment of pain. Recently, a number of controlled trials with selective serotonin and noradrenaline reuptake inhibitors, such as venlafaxine, milnacipran and duloxetine, suggest that these drugs are as effective in relieving pain as TcA and better tolerated. The analgesic effect of antidepressants seems to be independent of their antidepressant effect.