How do we treat cluster headache?

Cluster headaches are one of the worst pains known to humanity, mostly affecting men. On the third Cluster Headache Awareness Day, we asked cluster headache researcher and member of The Journal of Headache and Pain advisory board, Dr. Andrea Negro, to introduce us to current treatment options for cluster headache and the cutting edge research driving future treatment possibilities.

Cluster headache (CH) is an extremely painful headache disorder characterized by a daily and annual pattern, and by attacks of severe, strictly unilateral, periorbital pain accompanied by ipsilateral autonomic symptoms such as pupil constriction, tearing, runny nose, facial blushing, or swelling. During the bout periods, the attacks occur from once every other day to up to 8 times a day and lasts 15-180 minutes.

The cornerstones of cluster headache therapy are based on the tripod of preventative, transitional and acute treatments.

The cornerstones of cluster headache therapy are based on the tripod of preventative, transitional and acute treatments.

Prophylactic treatment aims to reduce episodes duration and number of attacks during the bouts, and maintain the patient attack-free over the expected duration of the cluster period. Unfortunately in the past 20 years no major advances have been made and today the prophylactic treatment is still based on empirical data of clinical efficacy rather than on a pathophysiological understanding of this disorder.

Treatments with a good clinical experience for the prevention of CH include verapamil, lithium, and topiramate. Prophylactic therapy usually becomes effective quite rapidly but total attack suppression is not always achievable and patients need to wait for the natural ending of the bouts.

Moreover, at the effective therapeutic dosage required for CH prevention, those drugs are often associated with severe adverse events such as bradycardia, hypotension, constipation, dizziness, and impotence.

The administration of prophylactic drugs in episodic CH should be maintained during the cluster period and the doses should be gradually lowered after the acute phase, whereas chronic CH patients should not reduce maintenance medications. Patients with active CH require close follow-up both to monitor the efficacy and the toxicity of maintenance treatments.

A short-term transitional steroids therapy, initially administered together with CH preventive treatment, can induce headache-free or near headache-free states in 70-80% of patients, acting as a bridging therapy between the time of CH bout diagnosis and the effective clinical action of the preventive drugs.

In order to quickly relieve the intense pain, the first-line acute treatment is currently based on 100% oxygen inhalation and/or subcutaneous injection of the drug sumatriptan.

After more than 30 years since its discovery, the neuropeptide calcitonin gene-related peptide (CGRP), which increases during CH attacks, is now firmly established as having a key role in CH. CGRP-targeted therapies represent the new frontiers for both episodic and chronic CH treatment.

Two monoclonal anti-CGRP antibodies, galcanezumab and fremanezumab, have proven efficacy, safety and tolerability in Phase 2 studies. At this time, both the drugs are under evaluation in Phase 3 clinical trials.

Those drugs represent a major breakthrough in CH treatment. All prophylactic treatments recommended by international guidelines have other primary indications and their use for CH is off-label. Also sumatriptan, which is now considered the mainstay for CH acute treatment, was originally investigated for another primary headache, migraine. The monoclonal anti-CGRP antibodies are the result of 30 years of research and represent the first class of drugs specifically developed for the treatment of cluster headache.

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