The aim of the study was to investigate the influence of duloxetine on clinical parameters and antinociceptive mechanisms in 46 patients with chronic migraine (CM). In addition to a clinical examination, we performed a neurophysiological investigation which included blink reflex (BR) and nociceptive flexion reflex (NFR) tests. From the beginning of the treatment with duloxetine (60 mg/d) to the third month of treatment, the number of days with headache decreased from 25,8±5,3 to 10,5±3,9 (p<0,001); the frequency of migraine attacks/month decreased from 11,3±3,8 to 6,8±2,5 (p<0,001); the amount of analgesic tablets used per month decreased from 46,6±14,7 to 8,5±10,6 (p<0,001). The reduction of the number of days with headache by more than 50% and more than 30% was noted in 50% and 57,5% of patients, respectively. The treatment with duloxetine resulted in the significant increase of the pain and NFR thresholds as well as in the normalization of the RIII threshold and its habituation in BR. These results confirmed the role of duloxetine in increasing of the noradrenergic and serotonergic activity of brain antinociceptive systems in patients with CM. The clinical effectiveness of duloxetine can be explained by its multilevel modulatory influence on the pathogenetic mechanisms of CM including the activity of antinociceptive systems of the brainstem and of brain nociceptive systems through the decrease of central sensitization.