Neurobiology of Chronic Migraine

Objective To present a systematic review of the present status of knowledge about the neurobiological mechanisms underlying transformation of episodic migraine into chronic migraine. Results Chronic migraine (CM), formerly known as transformed migraine, is a headache disorder that affects 2–3% of the general population. It is particularly frequent in tertiary care structures and is an important clinical problem for headache specialists. Analgesic overuse, sleep disturbances, depression, and anxiety are often comorbid with CM. The costs and burden of CM are significant. The pathophysiology of CM is still poorly understood. Within the last 2 decades there has been an explosion of new information on the mechanisms underlying chronic pain. Neurobiological studies have provided new insights into the pathogenesis of chronic migraine. Genetic factors play an important role in CM but the types and the number of genes involved in the disease are, at present, unclear. Certain features of chronic migraine, namely, increased headache frequency, expansion of headache area, and cutaneous allodynia, may imply sensitization of nociceptive neurons in the trigeminal pathway. Neurophysiological studies have shown that repetitive activation of the trigeminal nerve can lead to a biological and functional change in trigeminal nucleus caudalis neurons, characterized by a decrease in nociceptive threshold and receptive field expansion. Results from a number of experimental studies 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 migraine associated with analgesic overuse. Hypothalamic involvement may be a key feature of chronic migraine. Neuroendocrine studies have shown an abnormal pattern of hormonal secretion in the disease and suggested a possible hyperdopaminergic state in patients with CM. Finally, MRI studies have provided evidence that CM is associated with a progressive impairment in iron homeostasis within the periacqueductal gray, a centre of the descending antinociceptive neuronal network. Conclusions Despite no clear explanation of the mechanism underlying migraine transformation, experimental data suggest that the process is related to a progressive sensitization of the cerebral antinociceptive systems. Abnormal modulation of these systems may explain the shift of the migraine phenotype from episodic to chronic headache. The neuronal plastic changes in chronic migraine make the antinociceptive systems an important target for several types of interventions.