Decrease of Gray Matter Volume in the Midbrain is Associated with Treatment Response in Medication-Overuse Headache: Possible Influence of Orbitofrontal Cortex.

Medication-overuse headache (MOH) is a chronic form of headache and represents a severe complication of migraine in which an excessive intake of symptomatic drugs (analgesics, triptans, combination analgesics, etc.) is hypothesized to be involved in the shift from an episodic into a chronic form of headache. Indeed, the current diagnostic criteria of the Headache Classification Subcommittee of the International Headache Society (Olesen et al., 2006) requires that the primary headache develops or significantly worsens during medication overuse. This implies that when cessation of the medication overuse is realized through a withdrawal treatment, the chronic headache should return to an episodic pattern. Unfortunately, in clinical practice, this is true only in part, as a consistent percentage of patients remain in a chronic condition, revealing that the pathogenesis of MOH is more complicated than it appears and not completely understood.

From a pathogenic point of view, it is conceivable that an excessive intake of symptomatic drugs up to the point of medication overuse could interfere with brain structures involved in pain control. Neurophysiological studies demonstrated a widespread facilitation in pain responses at cephalic and extracephalic sites, coupled with a defective functioning of supraspinal structures, including the subnucleus reticularis dorsalis, involved in supraspinal descending control of pain (Perrotta et al., 2010). Neuroimaging studies demonstrated metabolic abnormalities in cortical areas involved in reward behaviors that are dysfunctioning in drug dependence, such as orbitofrontal cortex (Fumal et al., 2006). Interestingly, it was demonstrated that, in subjects who clinically improved after withdrawal detoxification treatment, these metabolic and neurophysiological abnormalities rapidly reverted to a condition close to that of subjects with episodic migraine (Fumal et al., 2006; Perrotta et al., 2010).

Riederer, Sándor, and colleagues have published an interesting paper that focuses attention on the structural changes of gray matter in subjects with MOH who underwent a detoxification program, by using a voxel-based morphometry (VBM) method, a technique devoted to identifying structural changes in brain structures.

In previous VBM work (Riederer et al., 2012), Riederer and colleagues demonstrated, in MOH patients compared to healthy control subjects, decreased gray matter in orbitofrontal cortex and increased gray matter in midbrain areas involved in the diffuse system of pain control, including periaqueductal gray matter, subnucleus reticularis dorsalis, and rostroventromedial medulla. These data permitted the hypothesis that in MOH subjects, neurophysiological and metabolic abnormalities are sustained by structural changes in the central nervous system. In the current study, the same authors demonstrated that subjects who responded to detoxification treatment showed a significant reduction in the previously increased midbrain gray matter when compared to ones in whom detoxification treatment failed to clinically improve headache, and that the magnitude of the reduction was positively correlated with the magnitude of the clinical improvement. In addition, no change in the reduced orbitofrontal cortex gray matter was detected after detoxification treatment, but extensive reduction in the orbitofrontal cortex before detoxification treatment correlated with less clinical improvement from the treatment.

Adding to metabolic and neurophysiological evidence, this paper significantly contributes, in my opinion, to the understanding of the mechanisms involved in chronification of episodic forms of migraine. The authors describe a treatment-dependent structural change in midbrain gray matter, probably reflecting a plastic rearrangement of neuronal networks involved in the diffuse descending supraspinal control of pain and coupled with a stable structural change in pivotal areas for drug dependence. Taken together, neurophysiological, metabolic, and structural evidence seems to support the hypothesis that in a subgroup of predisposed migraineurs, the excessive intake of symptomatic drugs could interfere with the functional balancing of the diffuse supraspinal control of pain, shifting an episodic form of migraine into a chronic form. To better understand the role of medication overuse in the pathophysiology of headache pain chronification, further studies should be done to evaluate the rare patients with chronic forms of migraine without medication overuse compared with MOH subjects, free from prophylactic treatment.