**3.1. Physiopathology of migraine**

Despite being the most common cause of headache, the underlying pathogenesis of migraine is not known and every day, new data is being made available which aid in the clarification of the possible processes behind such a major public health problem.

Once considered a cephalalgia of vascular origin involving intracranial blood vessel dilatation, recent data reveals that the physiopathology of migraine is much more complex; abnormal modulation of brain nociceptive systems [12], brain excitability, recurrent activation, and sensitization of the trigeminovascular pathway [13] all work together not only to produce but also to prolong the migraine.

The integration of the above-mentioned factors is shown in **Figure 1**, where the interaction and upregulation of each element over the other is made clear.

Moreover, **Figure 1** demonstrates why there are so many available migraine treatments, as each one has to work on a very narrow cluster of the whole pathogenic chain and why the effect of a particular therapy may diminish over time due to the upregulation and potentiation between different pathological events associated with migraine.

The good news behind such a complex physiopathology is the high number of therapeutic targets available to work with, rendering the therapeutic options almost infinite. Although the ideal treatment would be one that could act over all the mechanisms, or at least the most important one, unfortunately, such a treatment is far from being available, and current knowledge points to what seems to be the convergence point of all migraine pathogenic mechanisms: serotonin [14]. Abnormally low levels of this important neurotransmitter seem to be the cause of at least two of the pathological aspects: blood vessel dilation and brain hyperexcitability; hence, it is not surprising to find that there is a remarkable therapeutic effect by serotonin agonists on migraine.

**Figure 1.** The pathways of migraine [11].

#### **3.2. Physiopathology of tension-type headaches**

Even though migraine represents a major public health concern and is the leading cause of headache, tension-type headache should not be underestimated since it represents the second most common cause of cephalalgia with a prevalence of 46.9% in the general population [15], and provides the potential for a great field of study as tension-type headaches may be present in an acute scenario (known as episodic tension-type headache) or chronically, being called in such cases chronic tension-type headache. The most interesting fact regarding this dual presentation profile is that in some people tension-type headache remains acute and sporadic while some others progress toward a chronic condition. At the initial stage, both episodic and chronic tension-type headaches share a common pathophysiological pattern associated with scalp and head muscles chronically contracting as well as certain neck movements [16], these are usually identified as the triggers and are the targets for therapy in the past; however, recent investigations have shown that chronic muscle contraction alone is not enough to cause a pain crisis, but it also includes the presence of central nervous system factors such as a hypersensitivity to pain stimuli which causes a tension-type headache to evolve from just a simple contraction [17] to a chronic disorder affecting quality of life [18].

It is possible that at the very beginning all tension-type headaches begin this way but when there is increased excitability of the central nervous system generated by repetitive and sustained pericranial myofascial input [19] permanency occurs and upregulation creates a cycle of chronic tension-type headache, with lower stimuli requirements needed to trigger the next pain crisis. At the molecular level, chronic tension-type headache has been associated with low serotonin levels [20] acting as an upregulator in the case of migraine, on the other hand, there is the recent description of nitric oxide playing a role in both migraine and tension-type headaches, acting as a cranial and extracranial blood vessel dilator as well as a central nervous system sensitizer, these findings have led to a hypothesis about a common pain pathway shared by all primary chronic cephalalgias or at least between the two major groups, migraine and chronic tension-type headache [21].
