**6. New directions in the treatment of primary headaches**

**Figure 4.** LF/HF ratio in study groups.

60 Current Perspectives on Less-known Aspects of Headache

crine activity, immune, behavioral, and cognitive functions.

system [117–121]. Moreover, the ANS exhibits a circadian variation [122].

HRV is associated with highly functional prefrontal cortex inhibitory activity over subcortical structures that make the body to well adapt to the environment. Low HRV is associated with reduced prefrontal inhibitory control over subcortical structures and failure to recognize safety signals [104]. Failure of inhibition leads to continue to process fear information and is linked with anxiety and depression [115]. Chronic psychological stress and depressed mood have been shown to be associated with SNS dominance and vagal withdrawal, highlighted by decreased HRV [115, 116]. In our study, we found an increased frequency of anxiety and depressive symptoms in migraine patients, especially in migraine with aura group [114]. Individuals with high level of stress, anxiety, and depression display an imbalance between PNS and SNS activities. Prolonged stress may influence health via several different pathways, i.e., alterations in autonomic nervous system (increased SNS and decrease PNS), neuroendo‐

Many other factors such as alcohol, nicotine, physical exercise, age, gender, diabetes, hyper‐ tension, cardiovascular disease, sleep apnea, chronic respiratory disease, or medications (sex steroid hormones, antidepressants, μ‐ blockers, etc.) may influence the autonomic nervous

The ANS involvement during the premonitory phase of a migraine attack is suggested by many symptoms and signs with potential involvement of the hypothalamus (depression, irritability, fatigue, food cravings, and increase yawning), brainstem (neck stiffness), and cortex (abnormal sensitivity to light, sound, and smell) [123]. Nausea, vomiting, dizziness, cutaneous vasocon‐ striction or vasodilation, conjunctival injection, lacrimation, nasal congestion, rhinorrhea, eyelid edema, piloerection, and diaphoresis can occur during pain phase [108, 109]. Also accompanying psychological and cognitive symptoms can appear—inability to organize

It is classically accepted that migraine may respond to few different pharmacological agents such as pain‐relieving medications (like triptans) in acute phase and preventive medication like antiepileptics (like topiramate), CH responds to oxygen and parenteral triptans, while verapamil has the most success for prevention. Paroxysmal hemicrania responds to indome‐ thacin. SUNCT/SUNA responds to lamotrigine and topiramate. Hemicrania continua respond to indomethacin [136].

#### **6.1. Neurostimulation**

A promising and rather new venue in headache treatment seems to be represented by neuromodulation of pain central system and autonomic pathways. These noninvasive methods may provide relief in patients with chronic and pharmacoresistant forms of headache. Therefore, it was reported that transcutaneous stimulation of the parasympathetic nerve system via the vagus nerve can abort migraine attacks [137]. Vagal nerve stimulation represents a well‐established nonpharmacological strategy in epileptic patients with intractable seizures and also in depressed patients. Some cohorts of epileptic patients with implanted VNS have shown improvement in their migraine symptoms, but the eventual causality with seizure frequency reduction still needs to be debated also [138]. Similarly, patients known with migraine and treated with VNS for depression experienced an improvement in the migraine attacks [139]. Yet, further studies need to clarify the exact correlation between VNS effects and migraine mechanisms.

Recently, it has been shown that patients with CH seem also to benefit from noninvasive VNS, with improvement of their initial condition of approximately 50% [140]. On the other hand, occipital nerve stimulation (ONS) has proved favorable clinical results in the treatment of refractory chronic CH in well‐documented cases, but there are still limited studies in this direction. The hypothalamic activation during cluster attacks led to the introduction of deep brain stimulation (DBS) technique for refractory CH, with rather positive effects. Still, there is need of further confirmation of this method in CH, in terms of targeted anatomo‐functional centers and patients selection in order to have a good risk/benefit outcome [141, 142].

#### **6.2. Modulation of signaling molecules**

Migraine is considered as a syndrome of chronically low central serotonin system with consequent 5‐HT receptor hypersensitivity, with migraine attacks triggered by a sudden increase in 5‐HT release [143]. Therefore, medication targeting specific serotoninergic path‐ ways showed its efficiency in migraine acute treatment. Triptans are selective serotonin agonists, specifically acting at 5‐hydroxytryptamine 1B/1D/1F (5‐HT1B/1D/1F) receptors on intracranial blood vessels and sensory nerve endings. The first combination product of a triptan and a nonsteroid anti‐inflammatory drug (naproxen) was approved by the U.S. Food and Drug Administration in April 2008. It has been proven that migraineurs who experienced poor response to a short‐acting triptan, the combination of sumatriptan/naproxen sodium reported more effective results in pain reduction and migraine‐associated symptoms of photophobia and phonophobia [144].

New prevention strategy via biochemical signaling in migraine prevention is based on monoclonal calcitonin gene‐related peptide (CGRP) antibodies to CGRP are effective in migraine prophylaxis [145]. As shown previously, robust data showed that neuropeptides present in the perivascular space of cranial vessels are important mediators of nociceptive input during migraine attacks. Pituitary adenylate cyclase‐activating polypeptide (PACAP) is present in sensory trigeminal neurons and may modulate nociception at different levels of the nervous system. It has been proposed that the PAC(1) receptor represents a possible signaling pathway implicated in migraine and may be a future pharmacological target in migraine treatment [146].

The precise implication of the hypothalamus in premonitory phases of migraine and also during migraine attacks is discussed. Therefore, novel targets may include hypothalamic peptides such as orexine, which interferes with trigeminal nociceptive activity and cortical spreading depression–the well‐known neural phenomena in the prodromal phase of mi‐ graine [147]. Interestingly, Botulinum toxin A was associated with a small or modest benefit for chronic daily headaches and chronic migraines, reducing headache episodes per month [148].

#### **6.3. Genetic therapies**

like antiepileptics (like topiramate), CH responds to oxygen and parenteral triptans, while verapamil has the most success for prevention. Paroxysmal hemicrania responds to indome‐ thacin. SUNCT/SUNA responds to lamotrigine and topiramate. Hemicrania continua respond

A promising and rather new venue in headache treatment seems to be represented by neuromodulation of pain central system and autonomic pathways. These noninvasive methods may provide relief in patients with chronic and pharmacoresistant forms of headache. Therefore, it was reported that transcutaneous stimulation of the parasympathetic nerve system via the vagus nerve can abort migraine attacks [137]. Vagal nerve stimulation represents a well‐established nonpharmacological strategy in epileptic patients with intractable seizures and also in depressed patients. Some cohorts of epileptic patients with implanted VNS have shown improvement in their migraine symptoms, but the eventual causality with seizure frequency reduction still needs to be debated also [138]. Similarly, patients known with migraine and treated with VNS for depression experienced an improvement in the migraine attacks [139]. Yet, further studies need to clarify the exact correlation between VNS effects and

Recently, it has been shown that patients with CH seem also to benefit from noninvasive VNS, with improvement of their initial condition of approximately 50% [140]. On the other hand, occipital nerve stimulation (ONS) has proved favorable clinical results in the treatment of refractory chronic CH in well‐documented cases, but there are still limited studies in this direction. The hypothalamic activation during cluster attacks led to the introduction of deep brain stimulation (DBS) technique for refractory CH, with rather positive effects. Still, there is need of further confirmation of this method in CH, in terms of targeted anatomo‐functional

centers and patients selection in order to have a good risk/benefit outcome [141, 142].

Migraine is considered as a syndrome of chronically low central serotonin system with consequent 5‐HT receptor hypersensitivity, with migraine attacks triggered by a sudden increase in 5‐HT release [143]. Therefore, medication targeting specific serotoninergic path‐ ways showed its efficiency in migraine acute treatment. Triptans are selective serotonin agonists, specifically acting at 5‐hydroxytryptamine 1B/1D/1F (5‐HT1B/1D/1F) receptors on intracranial blood vessels and sensory nerve endings. The first combination product of a triptan and a nonsteroid anti‐inflammatory drug (naproxen) was approved by the U.S. Food and Drug Administration in April 2008. It has been proven that migraineurs who experienced poor response to a short‐acting triptan, the combination of sumatriptan/naproxen sodium reported more effective results in pain reduction and migraine‐associated symptoms of photophobia

New prevention strategy via biochemical signaling in migraine prevention is based on monoclonal calcitonin gene‐related peptide (CGRP) antibodies to CGRP are effective in

to indomethacin [136].

62 Current Perspectives on Less-known Aspects of Headache

**6.1. Neurostimulation**

migraine mechanisms.

and phonophobia [144].

**6.2. Modulation of signaling molecules**

Genetic studies have highlighted a potential role in the etiopathogenesis of primary headaches for several genes related to vascular, neuronal, and neuroendocrine mechanisms. Therefore, recent data showed the implication of new genes, like methylenetetrahydrofolate reductase (MTHFR), potassium channel, subfamily K member 18 (KCNK18), transient related potential vanilloid type 1 (TRPV1), transient related potential vanilloid type 3 (TRPV3), hypocretin (orexin) receptor 1 (HCRTR1), and hypocretin (orexin) receptor 2 (HCRTR2), both in migraine and cluster headache. Of course, further preclinical and clinical data need to confirm the precise place and indication of genetic intervention when addressing primary headaches, thus promoting the multifactorial determination of this pathology [149].

#### **6.4. Multidisciplinary nonpharmacological interventions**

Behavioral and psychological coaching in chronic headache patients in a multidisciplinary setting may foster treatment adherence and improve the quality of life in these patients. It is considered that behavioral therapy combined with pharmacological intervention (for example, beta blocker alone) renders more effective treatment [150].

The above‐mentioned directions of treatment in primary headache highlight the complexity of the pathogenic mechanisms of this pathology and the need for further studies to address therapeutic strategies adapted to individual condition.
