A defect in serotonergic analgesia and a hyperalgesic state are proposed as features common to headache and fibromyalgia. The benefit to both migraine and fibromyalgia from inhibiting ionotropic N-methyl-D-aspartate receptor activity implies that redundant hyperalgesia-related neuroplastic changes are crucial for severe or chronic migraine and primary fibromyalgia. The fact that migraine and primary fibromyalgia share some pivotal set-up of serotonergic and excitatory amino acid systems led us to analyse epidemiological data supporting the hypothesis that analgesic disruption and a consequent hyperalgesic state are mechanisms of both migraine and fibromyalgia. Beyond demonstrating the comorbidity between migraine and primary fibromyalgia, the data suggest that migraine may represent a risk factor for fibromyalgia.