Histamine and migraine revisited: mechanisms and possible drug targets

OBJECTIVE: To review the existing literature on histamine and migraine with a focus on the molecule, its receptors, its use in inducing migraine, and antihistamines in the treatment of migraine. BACKGROUND: Histamine has been known to cause a vascular type headache for almost a hundred years. Research has focused on antihistamines as a possible treatment and histamine as a migraine provoking agent but there has been little interest in this field for the last 25 years. In recent years two additional histamine (H(3) and H(4)) receptors have been discovered and a series of non-sedating antihistamines have been developed. It is therefore timely to review the field again. METHODS: For this review the PubMed/MEDLINE database was searched for eligible studies. We searched carefully for all articles on histamine, antihistamines and histamine receptors in relation to migraine and the nervous system. The following search terms were used: histamine, migraine disorders, migraine, headache, antihistamines, histamine antagonists, clinical trials, induced headache, histamine H(3) receptor, histamine H(4) receptor and pharmacology. Four hundred thirty-six titles were read, 135 abstracts were read, 112 articles were read in full and 53 articles were used in this review. Review process resulted in 12 articles added to a total of 65. FINDINGS: Early studies of H(1) and H(2) antihistamines lack scientific strength and show conflicting results. Most of the antihistaminic drugs used in these trials bind also to other receptors which makes it difficult to conclude on the antihistaminic effect. Histamine is an efficient inducer of migraine attacks in migraine patients by an H(1) mechanism most likely extracerebrally. These findings merit further investigation of antihistamines in clinical drug trials. The H(3) and H(4) receptors are found in primarily in CNS and immune tissues, respectively. H(3) is likely to be involved in antinociception and has been linked with cognitive, neurodegenerative and sleep disorders. The only marketed H(3) agent, pitolisant, is a brain penetrant H(3) antagonist/inverse agonist which increases central histamine and causes headache. The experimental H(3) agonist N(α)-methylhistamine has shown promising results as a migraine preventative in studies of uncertain quality. With the current limited knowledge of the H(4) receptor it is questionable whether or not the receptor is involved in migraine. CONCLUSION: There is insufficient support for first generation antihistamines (both H(1) and H(2)) as preventive migraine medications and sedation and weight gain are unacceptable side effects. Non-sedating H(1) antihistamines need to be appropriately tested. Central H(3) receptors seem to have a role in migraine that merit further investigation. The histaminergic system may be a goal for novel migraine drugs.