Central sensitisation phenomena have been well recognized in the development of migraine attacks and tension type headache. It is also known that headache frequency is related to sensitization. Though some studies have focused on the effects of symptomatic treatment on allodynia, few reports have described the action of preventive agents on the facilitating factors for central sensitisation. In this study we aim to review the factors concurrent with an increase in central sensitisation, in view of the choice of preventive agents for primary headaches. Central sensitisation phenomena are increased in pain syndromes with psycho-pathological co-morbidities. For instance, sleep disorders are a frequent symptom in headache, prevailing in chronic forms and in patients with psychiatric comorbidity. Sleep deprivation is also a factor producing hyperalgesic changes. It is known that symptoms attributable to central sensitization are diffusely pronounced in fibromyalgic (FMS) patients, and that FMS co-morbidity is frequent in primary headaches and associated with higher frequency and poorer quality of life. We report our preliminary experience in a group of 20 chronic migraine patients, treated with duloxetine 60 mg/die vs a self-management program including stretching (relaxation training) and exercise (cervical-dorsal flexion and rotation) to decrease strength and flexibility of muscles of cervical and dorsal spine headache patients. Both the treatments were effective on headache frequency and pericranial tenderness, although FMS comorbidity significantly reduced their efficacy on migraine and quality of life. The whole spectrum of action of pharmacological and non pharmacological treatments on central sensitisation mechanisms, and on their facilitating factors, should be taken into account for the best preventive therapeutic approach of primary headaches.