Cluster headache (CH) is one of the most painful medical conditions known to humans … frequently described as feeling like a “red hot poker in the eye.”

Cluster headache (CH) is one of the most painful medical conditions known to humans with a sticking and unmistakable phenotype characterized by unilateral, sharp pain frequently described as feeling like a “red hot poker in the eye” rapidly reaching an excruciating intensity. The headache episodes typically last between 15 and 180 minutes and can occur up to 8 times a day. The attacks are accompanied by at least one of the cranial autonomic symptoms (such as lacrimation, redness of the eye, runny nose or blocked nose) and/or sense of restlessness.

As the name suggests, cluster headache attacks are grouped in bouts occurring once or twice per year and lasting from a few weeks to a few months at a time (episodic cluster headache). One of the most fascinating features of this condition is the timing of occurrence of these headache periods, which peak during seasonal changes, particularly around solstices and equinoxes.

During the bouts, the painful episodes occur with clock-like precision throughout the 24-hour period with a preponderance of attacks during the sleep phase. Unfortunately, approximately 10–20% of patients may develop the chronic form of cluster headache, which presents with daily or almost daily attacks without any significant remission period.

CH is considered to be a multifactorial disorder, where a combination of genetic and environmental factors may play a role. Although several studies have focused on the identification of the “cluster headache gene,” the results of these studies are inconclusive and at present no gene mutations have been linked with increased risk of cluster headache. Larger genetic studies are currently underway and may shed lights on the role of genetics in cluster headache.

Environmental factors of extreme interest include the effect of change in number of daylight hours (photoperiods), which may act as the initiation event of the cluster periods and may explain the peak occurrence of bouts around solstices and equinoxes. Extreme cold and warm temperature may also constitute relevant factors in cluster headache period onset.

Once in a cluster period, factors like alcohol, increased body temperature, sleep-wake cycle, hypoxia, and nitroglycerine can consistently trigger an attack. Furthermore factors such as cigarette smoking, caffeine consumption and head trauma may be significantly more associated with cluster headache rather than with other headache disorders.

Advances in understanding cluster headache

Significant progress has been made in the understanding of the pathophysiology of cluster headache. The clock-like periodicity, the seasonal pattern of the attacks, alongside the occurrence during the sleep phase and the presence of autonomic symptoms, underpin a dysfunction in our body clock, the posterior hypothalamus.

The posterior hypothalamus is implicated in pain processing and pain modulation and several lines of research support the role of the posterior hypothalamus in cluster headache.

This brain structure is implicated in pain processing and pain modulation and several lines of research support the role of the posterior hypothalamus in cluster headache. However, unlike previously thought, the hypothalamic derangement seen in cluster headache, rather than be the cluster headache generator, is likely to create a permissive state. This means that it allows abnormal firing of the neuronal loop responsible for relaying pain signals to the brain in cluster headache, called the trigemino-autonomic reflex.

Recent studies are trying to unravel the role of neurochemical products released on activation of these neuronal structures in cluster headache in order to identify novel potential therapeutic targets.

The orexinergic system is one of the most fascinating potential targets. These neurons are found in the hypothalamus and loss of orexinergic fibers is linked with sleep disorders such as narcolepsy. The Orexin system is implicated in a variety of functions including sleep-wake cycle, autonomic function and nociceptive processing. With their projections to the trigeminal nuclei and the spinal cord they seem to modulate trigeminal pain processing.

It could be postulated that part of the hypothalamic dysfunction demonstrated in cluster headache involves a derangement of the orexinergic system, suggesting that this system could be a potential target for new cluster headache treatments.

Other neuropeptides, which are released during activation of the trigeminal and cranial parasympathetic systems, such as calcitonin gene-related peptide (CGRP) and the pituitary adenylate cyclase-activating peptide (PACAP) are increased during cluster headache attacks, suggesting they also have a role in cluster headache and potential new targets for the development of more disease specific treatments.

The recent meaningful advances in the understanding of cluster headache have prompted the development of new, more disease-specific treatments, which may potentially revolutionize the management of this terrible condition and be the dawn of a new era for sufferers.