Ramelteon in the Prophylaxis of Chronic Cluster
Headache-Case Report
Yukihiro
Hamada, Kazumasa Saigoh, Yoshiyuki Mitsui, Shoji Kikui, Takao Takeshima, Susumu
Kusunoki
Yukihiro
Hamada, Kazumasa Saigoh, Yoshiyuki Mitsui, Susumu Kusunoki, Department of
Neurology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi,
Osaka-Sayama, Osaka 589-8511, Japan
Shoji
Kikui, Takao Takeshima, Department of Neurology, Tominaga Hospital, 1-4-48,
Minatomachi, Naniwa-Ku, Osaka 556-0017, Japan
Correspondence to: Kazumasa Saigoh, MD, PhD, Department of
Neurology, Kinki University School of Medicine, 377-2 Ohno-Higashi,
Osaka-Sayama, Osaka 589-8511, Japan
Email: saigoh@k.email.ne.jp
Telephone: +81-723660221 Ext: 3553
Fax: +81-723664846
Received: December 9,
2014
Revised: February 6, 2014
Accepted: February 9, 2015
Published online: May 13, 2015
ABSTRACT
Cluster headache
is a primary headache characterized by severe pain with most attacks occurring
during sleep. This is a case report on the use of ramelteon as a treatment for
chronic cluster headache. A 42-year-old businessman, who had been experiencing
episodic cluster headaches for 10 years, was diagnosed with chronic cluster
headache in the past year during which time his activities of daily living had
been greatly reduced because of daily cluster headache attacks. We initiated
treatment with ramelteon (8 mg/day) prophylactically before sleep, and his
average attack frequency per day after taking the drug was less than that
before taking the drug. The elimination half-life of ramelteon is typically
under 2 h, whereas that of melatonin is typically 30 min. This difference in
the elimination half-life may have caused the better response to ramelteon
treatment than to melatonin. We conclude that ramelteon may be useful as a new
agent in both the prevention and prophylaxis of chronic cluster headache, when
attacks occur at the same time during the night and that cluster headache is
related to circadian rhythm.
© 2015 ACT. All
rights reserved.
Key words: Cluster headache; Ramelteon; Melatonin; Circadian
Rhythm; Prophylaxis
Hamada Y, Saigoh
K, Mitsui Y, Kikui S, Takeshima T, Kusunoki S. Ramelteon in the Prophylaxis of
Chronic Cluster Headache-Case Report. International
Journal of Neurology Research 2015; 1(1): 93-95 Available from: URL:
http://www.ghrnet.org/index.php/ijnr/article/view/964
INTRODUCTION
The clinical features of cluster headache (CH) are a headache that is
usually lateralized, often with prominent, cranial, parasympathetic autonomic
features, which are also lateralized and ipsilateral to the headache (ICHD-IIIβ:
3.1)[1]. Approximately 10%-15% of patients with chronic cluster
headache (CCH) do not have remission periods[2] (ICHD-IIIβ: 3.1.2)[1].
Unlike episodic cluster headache (ECH) attacks, which occur in periods lasting
from seven days to one year, separated by pain-free periods lasting at least
one month (ICHD-IIIβ: 3.1.1)[1], CCH attacks occur for more than one
year without remission or with remission periods lasting less than one month.
CCH is an
intractable headache and reduces the ability of the patient to perform
activities of daily living (ADLs). CCH occurs daily without remission periods.
CH may be caused by a decrease in nocturnal melatonin levels and a loss of
melatonin rhythm[3]. In a small double-blind, placebo-controlled
study in 20 patients with CH, melatonin reduced CH frequency compared with the
placebo[4]. Ramelteon is the first in a new class of sleep agents
and is a melatonin receptor agonist for both MT1 and MT2 receptors[5].
There are currently no studies describing the effectiveness of ramelteon in the
prophylaxis of CCH. To the best of our knowledge, this is the first report on
the use of ramelteon as a preventive treatment for CCH.
Method
We obtained informed consent from the patient for treatment with
ramelteon after explaining its side effects. The study was approved by our
hospital’s review board and was therefore performed in accordance with the
ethical standards laid down in the 1964 Declaration of Helsinki and all
subsequent revisions.
Headache
pain of parameters used to average attack frequency per day.
CASE REPORT
A 42-year-old businessman had been experiencing one-sided, episodic,
and excruciating headaches for 10 years. Seven years ago, he visited our
hospital for a check-up. He had no other diseases, and there were no abnormal
findings on brain magnetic resonance imaging. The headaches occurred three to
five times per day with lacrimation, rhinorrhea, and miosis on the affected
side, accompanied by a sense of restlessness and agitation. The headaches and
secondary symptoms continued for approximately 90 min every day during a
one-month period every summer. He was diagnosed with ECH as he fulfilled the
necessary diagnostic criteria[1]. We started therapy with 7 L/min
oxygen and 50 mg sumatriptan. The response to oxygen therapy was mild and
lasted for approximately 30 min, and treatment with sumatriptan by oral
administration was not effective in preventing the cluster attacks.
Four years ago, we
started sumatriptan treatment via 3 mg subcutaneous injection for the CH
attacks. The response to the subcutaneous sumatriptan injection treatment was
good and had a fast effect within approximately 10 min. Therefore, we taught
the patient to self-administer sumatriptan subcutaneously. Three years ago, the
ECH attacks began to occur daily from March to April, as well as during the one
summer month. Nevertheless, the patient continued to self-administer 3 mg
sumatriptan subcutaneously for the attacks.
A few months
before our follow-up period (Figure1), the CH attacks reduced in their
frequency with remission periods, and the response to subcutaneous sumatriptan
injection treatment remained very good.
However, the
period between CH attacks was eight months, which was different from before
because within one month, the attacks occurred again.
By 12 months
(Figure 1), the CH attacks were occurring throughout the 11 months without
1-month periods of pain-free remission. He was therefore diagnosed with CCH
because he fulfilled the criteria[1]. We then tried an alternative
treatment using verapamil 240 mg/day, lomerizine 10 mg/day, and sodium
valproate 600 mg/day. However, these agents were not effective against the CCH
attacks, and only subcutaneous sumatriptan treatment produced a satisfactory
response against the attacks. Following the use of prednisolone (0.5 mg/kg)
before sleeping, the attacks did not occur during the day but began to occur 2
h after going to bed every night. We hypothesized that his attacks were
connected with circadian rhythm and basic sleep disturbance and attempted using
prophylactic ramelteon (8 mg/day), administered every night before the patient
went to sleep. The patient’s average attack frequency per day was less after
taking the drug than that before taking the drug (Figure 1). His sleep
disturbance also returned to a normal rhythm. He did not experience any direct
or collateral side effects such as dizziness or daytime sleepiness with
ramelteon treatment. CH attacks are now very infrequent and occur only several
times a month. The patient continues to use ramelteon alone as an effective
treatment.
DISCUSSION
CHs are classified into two
subtypes: ECH and CCH. CCHs are rarer with only 10%-15% of cluster headaches
being classed as chronic[2]. CCHs are continuous, excruciating
headaches without pain-free intervals. CCHs are also intractable and adversely
affect the ability to perform ADLs. Melatonin may be involved in CH attacks.
Chazot et al[3] have reported a decrease in melatonin
secretion at night and disappearance of melatonin rhythm in patients with CH.
Plasma melatonin levels decreased and there was no melatonin rhythm either in
non-rapid eye movement sleep, rapid eye movement sleep, or waking during cluster
periods. However, plasma melatonin levels did not decrease and had normal
rhythm during remission periods[6]. Melatonin treatment for CH has
only been studied in a small, double-blind, placebo-controlled trial. This
trial reported a significant decrease in CH attacks in the melatonin-treatment
group when compared with the placebo group[4]. However, a more
recent double-blind, placebo-controlled trial using melatonin treatment for CH
did not report a significant difference in attacks[7]. Therefore, response
to melatonin treatment for CCH differs between reports[8,9].
Ramelteon is
the first in a new class of sleep agents and is a melatonin receptor agonist
with both high affinity and selectivity for melatonin MT1 and MT2 receptors
than for MT3 receptors. The activity of ramelteon at the MT1 and MT2 receptors
is believed to improve sleep and the maintenance of circadian rhythm that
determines the normal sleep-wake cycle[5]. The elimination half-life
of ramelteon is typically under 2 h, whereas that of melatonin is typically 30
min. The difference in the elimination half-life may cause a better response to
ramelteon treatment than to melatonin treatment.
Only one
previous case report in Japan has documented the effectiveness of ramelteon in
a patient with ECH[10]. This report used ramelteon for a very short
period. In our case, ramelteon was used in the patient with CCH for a longer
period. We suspect that ramelteon adjusted and stabilized the patient’s
melatonin level and circadian rhythm[11,12]. No other study has
shown the effectiveness of ramelteon in the treatment of CCH. Ramelteon may be
useful as a new agent in the preventive treatment of CCH when attacks occur at
the same time during the night and when CH is related to circadian rhythm.
Furthermore, ramelteon may be used at night prophylactically in CH.
Acknowledgments
This study was supported in part by the Ministry of Health, Labor, and
Welfare of Japan [Research on intractable diseases (H26-69)] and the Ministry
of Education, Culture, Sports, Science, and Technology of Japan (Grants-in-Aid
for Scientific Research, 24390225)
CONFLICT OF INTERESTS
The Authors have no conflicts of interest to declare.
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Peer
reviewer: Lidiane
Lima Florencio, São Paulo Univerisity, Brazil.
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