Certain features of chronic daily headache, namely, increased headache frequency, expansion of headache area, and cutaneous allodynia, may imply sensitization of central nociceptive neurons in the trigeminal pathway. Repetitive activation of the trigeminal nerve can lead to a biologic and functional change in trigeminal nucleus caudalis neurons, characterized by a decrease in nociceptive threshold and receptive field expansion. Suppression of the endogenous pain control system can facilitate the process of central sensitization. Evidence of such suppression in patients with chronic daily headache includes decreased platelet serotonin, up-regulation of 5-HT2A receptors, increased platelet nitric oxide production, and increased levels of substance P and nerve growth factor in the cerebrospinal fluid. Results from a number of animal experiments have indicated that chronic analgesic exposure leads to changes in serotonin content and density of 5-HT2A receptors in the central nervous system. This plasticity of the serotonin-dependent pain control system may accelerate the process of sensitization; a biologic outcome that is expressed clinically by the development of chronic daily headache associated with analgesic overuse.