Despite no clear explanation of the mechanism underlying chronic daily headache, sensitization of central nociceptive neurons is one possibility. Either prolonged activation of peripheral nociceptors or any factors that can alter the endogenous pain control system can trigger this process. A decrease in platelet serotonin has been observed in patients with chronic tension-type headache as well as migraine patients with medication-induced headache. It was also shown that chronic analgesic exposure led to changes in the serotonin content and the density of the 5-HT(2A) receptor in the cerebral cortex. The plasticity of the serotonin-dependent pain control system may facilitate the process of sensitization and results in the development of chronic daily headache.