The Efficacy of L-cysteine in Prevention of Cluster Headache. Randomized Intervention Trial With a Medical Device (Acetium® Capsules)

Background: Cluster headache belongs to a group of idiopathic headache entities, the trigeminal autonomic cephalalgias (TACs), all of which involve short-lasting, unilateral, severe headache attacks and typical accompanying autonomic symptoms. The life-time prevalence of cluster headache for adults of all ages is around 125/100,000, or approximately 0.1%, with clear male dominance (4:1). Prophylactic treatment is an important part of the total management of cluster headache patients, having twofold goals: i) to reduce the frequency, painfulness, and/or duration of headache attacks, and ii) to increase the effectiveness of abortive therapy. During the past several decades, a large number of optional modalities have been tested as preventive measures of cluster headache. Not unexpectedly, the effects of any such preventive therapies are highly variable, and in many patients, the attack frequency is not under satisfactory control. Many of these drugs also have untoward side effects that offset their potential benefits.

Recently, spontaneous case testimonials were received by Biohit Oyj from migraine patients (and one with cluster headache) reporting that our new medical device, Acetium™ capsule (containing 100mg l-cysteine, developed for inactivation of acetaldehyde in the stomach contents after alcohol intake), proved to be highly effective against their headache attacks. Their attacks disappeared almost immediately after onset of L-cysteine administration, all of them remaining in complete remission for several months up to several years.

These spontaneous testimonials prompted us to formulate a novel study hypothesis that could possibly explain this dramatic effect of L-cysteine in prevention of headache attacks, to be tested in this RCT. This novel hypothesis is starting from the fact that, in cluster headache (a vascular-type of headache), swelling and dilatation of the blood vessels is necessary to provoke the attack.

It is known that Nitric Oxide (NO) is the final trigger of vascular headache attack, operating through phosphorylated protein kinase G (PKG) and Ca2+ channels, slowing the influx of calcium into the cell, which leads to smooth muscle relaxation and vasodilation. Histamine is a potent inducer of NO Synthase, making NO available locally on the vasculature, acting through endothelial H1-receptors. Histamine is synthesized from histidine in tissue mast cells, which are ubiquitous cells and their activation e.g. in the meninges has long been suspected to be involved in generating migraine headaches. Finally, one of the potent liberators of histamine from the mast cells is acetaldehyde, which, in turn, is effectively inactivated by L-cysteine (Acetium capsule). This led us to rational that by eliminating acetaldehyde in the stomach, L-cysteine could block (or reduce below the threshold levels) histamine liberation from the tissue mast cells and ECL cells in the stomach, thus arresting its multitude of functions, of which vasodilatation is critically involved in the cluster headache attack.

Objective: To validate the novel hypothesis that daily use of L-cysteine (Acetium capsules, 100mg twice a day) is an effective means to decrease the frequency of (or completely abort) the headache attacks in patients suffering from cluster headache.