**Author details**

cortex leading to a decrease in intrinsic pain downregulation circuits and the development of chronic headaches such as MOH and modified migraine (MM) [105]. Such metabolic changes may be associated with the sensitization of the trigeminal and somatic nociceptive systems; another possible path leading to MOH was demonstrated by Ayzenberg et al. on triptan-

Furthermore, the mechanisms stated earlier may be connected to others both centrally and peripherally by a complex net of interactions currently unknown but feasible such as "*upregulation of calcitonin gene–related peptide, substance P, and nitric oxide synthase in trigeminal ganglia; expansion of receptive field and decreased nociceptive threshold of central trigeminal neurons; decrease in diffuse noxious inhibitory control; and increased susceptibility to develop cortical spreading depression (CSD). These changes indicate an increase in excitability of cortical and trigeminal neurons. The neuronal hyperexcitability may be the result of derangement of a central, possibly serotonin (5-HT) dependent, modulating control system. Experiments with animals with low 5-HT showed that the processes of CSD and trigeminal nociception are enhanced in this condition*" [107] as it has been

The available information clearly supports the theory that analgesics and painkillers play an active role in the chronification of headache, which is a real concern for the medical community considering the high number of available over-the-counter analgesics. Furthermore, primary therapies such as triptans are also involved in MOH development after chronic use and there is even weaker evidence to explain the underlying pathways that cause this occurrence. At the moment the most probable mechanism of triptaninduced MOH is "*induction of neural adaptations that result in a state of latent sensitization, which might increase sensitivity to migraine triggers"* [108], in addition, *"triptan administration promotes increased expression of neuronal nitric oxide synthase in dural afferents, which is critical for enhanced sensitivity to environmental stress, which is a biological basis for increased frequency* 

Certainly, current knowledge regarding MOH and other types of headache chronification caused by the use of therapy is still lacking although the results from many research reports are available. However, until a deeper scientific understanding is available regarding this relatively new entity, it becomes necessary to improve the diagnostic criteria and methods, enhance treatment protocols, and provide proper monitoring not only to chronic primary headache patients but also to each one suffering from a chronic pain

Until a more precise and wider scope of information is available, prevention remains the best, most cost-effective option used to prevent headache treatment abuse-related complications. When the disorder of MOH and drug-induced headache presents, the main treatment must be treatment withdrawal and even then the discussion on what is the best withdrawal method (stationary vs. ambulatory) still remains inconclusive [110]; as a preventive strategy, drug combinations must be avoided as much as possible and high-risk patients who develop MOH must be regularly evaluated to ensure that no late complications are showing up during

demonstrated by Bongsebandhu et al. in animal models.

induced MOH [106].

160 Pain Relief - From Analgesics to Alternative Therapies

*of headache following*" [109].

condition.

long-term treatment.

Silvia Ussai1 , 2 , 3 \* and Alessandro Rizzardo3

