The relief effects of ramelteon on refractory chronic migraine

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The relief effects of ramelteon on refractory chronic migraine

A 71-year-old female patient suffered from a chronic migraine for two decades. She never experienced insomnia problems before the first onset of a migraine. A migraine occurred 3-4 times per week, and each episode persisted around 4-8 hours. The pulsating pain was localised at right half of the head. The precipitating factors were the stress, increase in physical activities and sudden cold weather. The relieving factors included warm temperature, slower pacing of life and comfortable environment. The moderate or severe pain intensity was aggravated by or causing avoidance of increased physical activity. The residual symptom between the migraine episodes was the head tense feeling, but not achieving headache severity. The function remained well except avoiding exercise during and between the migraine episodes.


After going through the above case presentation, what do you think, could ramelteon alleviate a migraine?

  • Yes
  • No


The selective melatonin receptor agonistic effect of ramelteon is useful for insomnia. This study is about a refractory chronic migraine case, in which the patient had significant improvements in migraine after using ramelteon.


Medical History

No family history of headache was mentioned


Examination and Laboratory Investigations

The condition was diagnosed by the International Headache Society criteria for migraine. The computed tomography revealed no significant findings of other causes for headache, such as a tumour or haemorrhage.



She received many kinds of medications, such as aspirin, nonsteroidal anti-inflammatory drugs, triptans, ergots, anticonvulsants and glucocorticoids. However, the severity of migraine remained moderate (Migraine Disability Assessment Test [MIDAS] scores, 19) and the associated symptoms were a moderate headache, nausea, dizziness and sound sensitivity. The migraine also worsened her insomnia problems, with fragmented sleep and inadequate sleep duration as 1-2 hours (Insomnia Severity Index [ISI] score, 23). Moreover, she didn't have any comorbid mental disorder. Due to the fear of abusive potential associated with hypnotics, she chose to take ramelteon to relieve insomnia. The concurrent analgesic medicine for migraine was ibuprofen 400 mg/day. After two weeks treatment of ramelteon 8 mg/day, her sleep duration prolonged to 4-5 hours with less fragmentation. Also, her migraine severity started to decline (MIDAS scores, 11). After six months of ramelteon 8 mg/day treatment, the migraine became less severe (MIDAS scores, 6) with stable sleeping quality (ISI score, 14).



In this case, significant improvements were seen in migraine severity and insomnia after the use of ramelteon. Moreover, the patient didn't have insomnia before the first onset of migraine. Therefore, it could be speculated that the ramelteon had significant effects in migraine viz. mild.

Prolongation of sleep duration. The melatonin might relieve a headache via the following possible mechanisms, such as anti-inflammatory effect, free radical scavenging, reduction of the pro-inflammatory cytokine, membrane stabilization, nitric oxide synthase activity and dopamine release inhibition, GABA and opioid analgesia potentiation, glutamate neurotoxicity protection, neurovascular regulation,2 cytoprotection and antiallodynic action.3 The pineal gland which is the primary source of serotonin and melatonin, could also have a significant role in the analgesic effect.4 However, the clinical trial of melatonin administration did not show significant improvements in migraine severity,5 which suggested the modulation of melatonin receptor could be beneficial in exhibiting the analgesic effects.

The modulation of the serotonin system by the ramelteon would also relieve the pain sensation.2 Also, the chemical structure of ramelteon was similar to that of indomethacin, which is a kind of non-steroidal anti-inflammatory medicine.2 In the study of animal model, the antiallodynic and antinociceptive actions of melatonin have been observed through different kinds of pathways, when administered through intrathecal or intracerebroventricular routes. The use of ramelteon, MT1 and MT2 agonist, could also relieve the pain even lack free radical scavenger effects.3



The state-of-art treatment of refractory chronic migraine may include the ramelteon due to selective M1 receptor agonism.6 From the successful experience, in this case, the use of ramelteon can be considered for refractory chronic migraine with insomnia.



1. Reynoldson JN, Elliott E Sr, Nelson LA. Ramelteon: a novel approach in the treatment of insomnia. Ann Pharmacother 2008;42:1262-1271.
2. Peres MF, Masruha MR, Zukerman E, Moreira-Filho CA, Cavalheiro EA. Potential therapeutic use of melatonin in migraine and other headache disorders. Expert Opin Investig Drugs 2006;15:367-375.
3. Srinivasan V, Pandi-Perumal SR, Spence DW, Moscovitch A, Trakht I, Brown GM, et al. Potential use of melatonergic drugs in analgesia: mechanisms of action. Brain Res Bull 2010;81:362-371.
4. Toglia JU. Melatonin: a significant contributor to the pathogenesis of migraine. Med Hypotheses 2001;57:432-434.
5. Alstadhaug KB, Odeh F, Salvesen R, Bekkelund SI. Prophylaxis of migraine with melatonin: a randomized controlled trial. Neurology 2010;75:1527-1532.
6. Lionetto L, Negro A, Palmisani S, Gentile G, Del Fiore MR, Mercieri M, et al. Emerging treatment for chronic migraine and refractory chronic migraine. Expert Opin Emerg Drugs 2012;17:393-406.

Exploratory, Aspirin, ibuprofen, Ramelteon, Nonsteroidal anti-inflammatory drugs, Triptans, Ergots, Anticonvulsants, Glucocorticoids, Chronic migraine, Case study, Migraine Disability Assessment Test [MIDAS] scores, Insomnia Severity Index [ISI] score
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