Objective: To test the efficacy of the subcutaneous administration of histamine in cluster headache by undertaking an open clinical trial.
Results: In patient 1, cluster headache attacks disappeared 20 days after initiation of histamine treatment. After a 6-year follow-up, the patient has reported only one episode of cluster headache, which occurred three years after initiation of histamine treatment and lasted for a week. Mild pain attacks were located at the left periorbital region, occurred twice a day, lasted for 20 to 30 minutes, and were relieved by indomethacin (300 mg/day). In addition, the patient presented with mild conjunctival injection during pain attacks. Patients 2 and 3 reported that cluster headache attacks disappeared 14 and 8 days respectively, after histimine administration began, both remaining asymptomatic after a 5-year follow up.
Conclusion: The subcutaneous administration of histamine, at considerable low doses (1-10 ng), is effective and well tolerated for the prevention of cluster headache, presumably reflecting the operation of a local C fiber nerve ending-mast cell feedback loop, controlling processes such as neurogenic inflammation. Furthermore, this loop still functions when mast cells proliferate in an inflammatory condition. Taken together, these data suggest that vascular changes taking place during active cluster headache, far from being an epiphenomenon of the trigeminal activation, represent a necessary condition for the triggering of autonomic and clockwise characteristic features of cluster headache. Finally, histamine may represent a therapeutic alternative as a prophylactic treatment in cluster headache and migraine. Low-dose histamine therapy appears to be a novel and valuable clinical tool in neurovascular headaches.