The
tricyclic antidepressant amitriptyline is the only documented and most widely used prophylactic
drug for chronic
tension-type headache (CTTH). However, it is not fully clarified whether the
serotonin (5-HT) reuptake inhibition plays a major role for the
analgesic effect of
amitriptyline. To explore the importance of
5-HT reuptake inhibition for mechanism of action of the
analgesic effect of
amitriptyline we investigated platelet
5-HT levels during preventive treatment of CTTH with
amitriptyline, the
selective serotonin reuptake inhibitor citalopram, and placebo. Thirty-four patients with CTTH were given preventive treatment with
amitriptyline 75 mg/day, the selective
5-HT reuptake inhibitor
citalopram 20 mg/day, and placebo in a 32-week, double-blind, placebo-controlled, three-way crossover trial. Blood samples were collected in the last week of each treatment period. Platelet
5-HT was used as a measure of
5-HT reuptake inhibition and determined by high performance liquid chromatography. Area under the
headache curve was 308 (157-715) (median with quartiles in parentheses) with
amitriptyline and significantly lower than 377 (158-1121) with
citalopram (P = 0.04) and 441 (178-1408) with placebo (P = 0.002). There was no difference between
citalopram and placebo (P = 0.23). Platelet
5-HT was 0.4 (0.3-0.7) x 10(-18)mol/platelet with
citalopram, which was significantly lower than 1.7 (1.2-2.4) x 10(-18)mol/platelet with
amitriptyline (P < 0.001), and 3.5 (2.8-4.3) x 10(-18)mol/platelet with placebo (P < 0.001). The lower platelet
5-HT during treatment with
citalopram than
amitriptyline indicates that
5-HT reuptake was most effectively inhibited by
citalopram. In contrast,
amitriptyline was most effective in reduction of
headache. This suggests that the
analgesic effect of
amitriptyline in CTTH is not solely due to
5-HT reuptake inhibition and that other mechanisms such as
norepinephrine reuptake inhibition,
NMDA receptor antagonism, blockade of
muscarinic receptors and
ion channels should be addressed in the future research.