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A 41-year-old man came to our headache clinic with excruciating severe stitching pain in the left eye socket, observed for 20 years. Headache attacks were accompanied by nasal congestion, conjunctival injection, anxiety, and migraine manifestations such as nausea, vomiting, and phonophobia. There was no constant pain in the patient. The duration of the attacks of pain was about 60 minutes, and their frequency varied from two to three attacks per day. Attacks developed mainly during sleep.
The most likely diagnosis based on the clinical picture:
This post describes a clinical case of cluster headache treatable with ramelteon. According to our data, no articles in English on the use of ramelteon for the treatment of cluster headache have been previously published.
The patient had a history of excruciating severe stitching pains in the left orbit for 20 years. Headache attacks were accompanied by nasal congestion, conjunctival injection, anxiety, and migraine manifestations such as nausea, vomiting, and phonophobia.
Previously, the patient received subcutaneous sumatriptan (3 mg), inside sumatriptan (50 mg), inside eletriptan (20 mg), verapamil (maximum 240 mg / day), prednisone inside (maximum 30 mg / day), lithium (maximum 400 mg / day ), topiramate (maximum 100 mg / day) and valproic acid (maximum 200 mg / day). The response was observed only with subcutaneous administration of sumatriptan. Otherwise, the patient’s personal and family history was not burdened. The patient did not receive any medications and did not use drugs. The results of the assessment of basic vital signs, physical examination, neurological examination and laboratory tests were within normal limits. Symptoms observed in the patient met the criteria for cluster headache of the International Classification of Headaches-3 beta.
Headache attacks completely stopped with subcutaneous administration of sumatriptan, but the frequency of their development did not decrease. Verapamil (maximum 350 mg / day) was prescribed instead of topiramate, however, it also did not prevent the development of seizures. After a single intravenous administration of methylprednisolone (at a dose of 1000 mg), the patient received oral prednisone treatment (60 mg per day) for 5 consecutive days with a dose reduction over a 5-day administration period. Headache attacks completely stopped with the intravenous administration of methylprednisolone for 2 days, after which they occurred with a lower frequency from one to two times a day. Since headache attacks developed during sleep, treatment with ramelteon (at a dose of 8 mg) was started before bedtime and the use of verapamil was continued; intravenous administration of methylprednisolone and oral administration of prednisone were discontinued. Nocturnal seizures completely stopped during treatment with ramelteon, but seizures persisted in the early morning hours. The frequency of headache attacks decreased from about 10 times a week to 2-3 times a week. The intensity of the headache and the response to subcutaneous administration of sumatriptan did not differ from the corresponding indicators before the start of treatment with ramelteon. Ramelteon treatment was not associated with any undesirable effects. The cluster period ended 6 weeks after the start of treatment with ramelteon. The intensity of the headache and the response to subcutaneous administration of sumatriptan did not differ from the corresponding indicators before the start of treatment with ramelteon. Ramelteon treatment was not associated with any undesirable effects. The cluster period ended 6 weeks after the start of treatment with ramelteon. The intensity of the headache and the response to subcutaneous administration of sumatriptan did not differ from the corresponding indicators before the start of treatment with ramelteon. Ramelteon treatment was not associated with any undesirable effects. The cluster period ended 6 weeks after the start of treatment with ramelteon.
Ramelteon is a highly selective agonist of melatonin MT1 / MT2 receptors that mediate the circadian rhythm in mammals, which is used to treat insomnia. This drug has a slight affinity for MT3 receptor binding centers and other receptors in the brain (opiate, dopamine, benzodiazepine and serotonin). This explains the absence of significant adverse events and the risk of abuse of ramelteon or the development of dependence on it. In three clinical studies in patients with chronic insomnia, it was found that ramelteon at a dose of 8 mg effectively reduced the latent period of sleep without significant residual effects. The average half-life of ramelteon at a dose of 8 mg is higher than that of melatonin (1.4 hours compared to 30-50 minutes). After oral administration, ramelteon undergoes an intensive metabolism of the first passage in the liver. The half-life of the main metabolites of ramelteon, one of which is 20–100 times more active than melatonin, varies from 1 to 3 hours. In this patient, ramelteon did not prevent headache attacks in the early morning hours. The half-lives of ramelteon and its metabolites are suitable for the use of this drug to treat insomnia, but may be too short to prevent cluster headaches throughout the day.
An important role in the pathogenesis of cluster headache is played by the posterior part of the hypothalamus. In patients with cluster headache, a reduced level of plasma melatonin at night is recorded, indicating a possible role for melatonin in inducing seizures. Clinical and neuroendocrine data in favor of the participation of the hypothalamus in the development of cluster headache were confirmed in neuroimaging studies. The study by positron emission tomography showed that during attacks of cluster headache, the ipsilateral posterior part of the hypothalamus is activated. In addition, the results of voxel-based morphometry indicate a high density of cells in the gray matter of the posterior part of the hypothalamus from the ipsilateral side. In studies using proton magnetic resonance spectroscopy, a decrease in the ratios of N-acetyl aspartate / creatine phosphocreatine and choline / creatine phosphocreatine in the hypothalamus of patients with cluster headache was found. Based on an overnight decrease in plasma melatonin concentrations in patients with Leone cluster headache et al. evaluated the effectiveness of melatonin in the treatment of cluster headache. In a double-blind, placebo-controlled study involving 20 patients with cluster headache, patients receiving oral melatonin 10 mg per day showed a significant decrease in headache frequency (p <0.03) in the absence of side effects in both groups.
Данный случай демонстрирует, что рамелтеон обеспечивает немедленное подавление приступов кластерной головной боли в ночное время и не вызывает нежелательных эффектов. Таким образом, данный препарат можно применять в качестве вспомогательной профилактической терапии кластерной головной боли у пациентов с приступами во время сна. Рамелтеон не полностью предотвращает приступы головной боли в ранние утренние часы. Периоды полувыведения рамелтеона и его метаболитов также подходят для лечения бессонницы.
Intern Med 55: 2483-2485, 2016
A Cluster Headache Responsive to Ramelteon, a Selective Melatonin MT1/MT2 Receptor Agonist
Noboru Imai
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