Headache Medicine, v.3, n.2, p.61-69, Apr./May/Jun. 2012 61

Melatonin in headache disorders

A melatonina nas cefaleias

VIEW AND REVIEWVIEW AND REVIEW

VIEW AND REVIEW

Andre Leite Gonçalves, Reinaldo Teixeira Ribeiro, Mario F. P. Peres

Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil; Hospital Israelita Albert Einstein,

Instituto de Ensino e Pesquisa (INCE), São Paulo, SP, Brazil

Gonçalves AL, Ribeiro RT, Peres MF. Melatonin in headache disorders. Headache Medicine. 2012;3(2):61-9

ABSTRACTABSTRACT

ABSTRACT

Melatonin have diverse physiological functions, including the

control of circadian rhythms, sleep regulation, enhancement

of immunological functioning, free radical scavenging and

antioxidant effects, inhibition of oncogenesis, mood regulation,

vasoregulation, regulation of seasonal reproductive activity

and analgesia. Melatonin also have several actions within

the central nervous system and in the pathophysiology of

headaches, which include an anti-inflammatory effect, toxic

free radical scavenging, reduction of proinflammatory cytokine

up-regulation, nitric oxide synthase activity and dopamine

release inhibition, membrane stabilization, GABA and opioid

analgesia potentiation, glutamate neurotoxicity protection,

neurovascular regulation, serotonin modulation, and the

similarity of chemical structure to that of indomethacin. A

relation with seasonal and circadian pattern has been observed

in cluster an hypnic headache. The literature of headache is

convergent in pointing to low levels of melatonin in patients

with migraine and cluster headache. Treatment of headache

disorders with melatonin and other chronobiotic agents is

promising. Some trials showed that melatonin was effective in

cluster headache and migraine prevention but future studies

are necessary for the better understanding of the role of

melatonin in headache disorders treatment.

eywords: eywords:

eywords: Melatonin; Pineal gland; Migraine; Pathophysiology;

Treatment

RESUMORESUMO

RESUMO

A melatonina tem diversas funções fisiológicas, incluindo o

controle de ritmos circadianos, regulação do sono, melhoria

do funcionamento imunológico, varredura de radicais livres

e efeitos antioxidantes, inibição da oncogênese, regulação

do humor, vasoregulação, regulamentação da atividade

reprodutiva sazonal e analgesia. A melatonina também tem

várias ações dentro do sistema nervoso central e na fisio-

patologia das cefaleias, as quais incluem um efeito anti-infla-

matório e de limpeza de radicais livres tóxicos, a redução de

citocinas pró-inflamatórias, da inibição da atividade da óxido

nítrico sintase e da produção de dopamina, a estabilização

das membranas, potencialização da analgesia GABA e de

opioides, proteção contra a neurotoxicidade do glutamato,

regulação neurovascular, modulação da serotonina, além

de possuir estrutura química similar à da indometacina. Uma

relação com padrão sazonal e circadiano tem sido observada

na cefaleia em salvas e hipnica. A literatura de dor de cabeça

e melatonina é convergente em apontar a presença de baixos

níveis deste hormônio em pacientes com enxaqueca e cefaleia

em salvas. O tratamento das cefaleias com melatonina e

outros agentes cronobióticos é promissor. Alguns estudos

mostraram que a melatonina foi eficaz na cefaleia em salvas

e na prevenção da enxaqueca, porém futuros estudos são

necessários para comprovar seu beneficio no tratamento das

cefaleias.

alavrasalavras

alavras

chave:chave:

chave: Melatonina; Glândula Pineal; Enxaqueca;

Fisiopatologia; Tratamento

INTRODUÇÃO

Melatonin (5-methoxy-N-acetyltryptamine) was

discovered by Aaron Lerner in 1958. Melatonin synthesis

has been described in numerous peripheral organs, such

as the retina,

(1)

bone marrow,

(2)

skin,

(3)

platelets,

(4)

lymphocytes,

(5)

testis,

(6)

and in the gastrointestinal tract.

(7,8)

In these tissues melatonin seems to plays either an autocrine

or a paracrine role. Data on messenger RNA expression

62 Headache Medicine, v.3, n.2, p.61-69, Apr./May/Jun. 2012

GONÇALVES AL, RIBEIRO RT, PERES MF

of two key enzymes responsible for melatonin synthesis,

arylalkyamine-N-acetyltransferase and hydoxyindole-O-

methyltransferase, suggest that even more peripheral

organs may be able to produce this hormone.

(9)

Physiology of melatoninPhysiology of melatonin

Physiology of melatonin

The pineal gland is highly vascular and consists of two

types of cells: neuroglial cell and pinealocytes, which

predominate and produce indolamines (melatonin) and

peptides (such as arginine vasotocin). In the biosynthesis of

melatonin, tryptophan is converted by tryptophan hydroxylase

to 5-hydroxytryptophan, which is decarboxylated to serotonin.

Melatonin is produced after serotonin is catalyzed by two

enzymes (arylalkylamine N-acetyltransferase and

hydroxyindole-O-methyltransferase).

(10,11)

The production

and secretion of melatonin are mediated largely by

postganglionic retinal nerve fibers that pass through the

retinohypothalamic tract to the suprachiasmatic nucleus,

then to the superior cervical ganglion, and finally to the

pineal gland. This neuronal system is activated by darkness

and suppressed by light. The activation of alpha-1 and

beta-1-adrenergic receptors in the pineal gland raises

cyclic AMP and calcium concentrations and activates

arylalkylamine N-acetyltransferase, initiating the synthesis

and release of melatonin. The daily rhythm of melatonin

secretion is also controlled by an endogenous, free-

running pacemaker located in the suprachiasmatic

nucleus. Melatonin is able to enter every cell of the body

and readily crosses the blood-brain barrier and the

placenta. Melatonin is enzymatically degraded in the

liver by hydroxylation (to 6-hydroxymelatonin) and, after

conjugation with sulfuric or glucuronic acid and is finally

excreted in the urine as 6-sulphatoxymelatonin (aMT6s).

Analysis of urine by the ELISA method is used as a

measure of melatonin secretion, since it closely parallels

with the profile of plasma nocturnal melatonin

concentrations.

(12)

There is some evidence suggesting that

a seasonal variation exists in the synthesis of melatonin

in humans, the levels possibly being higher in winter than

in summer.

(13)

Melatonin is a potent antioxidant, which can exert its

action in directly or indirectly. In addition to its direct free

radical scavenging action, melatonin has been reported

to increase the activity of some important antioxidant

enzymes at molecular level, including superoxide

dismutase and glutathione peroxidase.

(14)

Also melatonin

decreases the activity of nitric oxide synthase, a pro-

oxidative enzime.

(15)

In fact melatonin can also scavenge

hydroxy radical, peroxil radical, peroxinitrite anion, and

singlet oxigen protecting cell membrane, proteins in the

cytosol and DNA in the nucleus.

PharmacologyPharmacology

Pharmacology

The half-life of melatonin in the serum is between 30

and 57 minutes.

(16)

Intravenously administered melatonin

is rapidly distributed and eliminated.

(17)

In normal subjects,

80 mg of melatonin orally administered promote serum

melatonin concentrations that were 350 to 10,000 times

higher than the usual nighttime peak, 60 to 150 minutes

later, and these values remained stable for 90 minutes.

(18)

Lower oral doses (1 to 5 mg), result in serum melatonin

concentrations that are 10 to 100 times higher than the

usual nighttime peak, within one hour after ingestion,

followed by a decline to base-line values in four to eight

hours. Very low oral doses (0.1 to 0.3 mg) given in the

daytime result in peak serum concentrations that are within

the normal nighttime range.

(19)

otential use of melatonin in analgesia:otential use of melatonin in analgesia:

otential use of melatonin in analgesia:

mechanisms of actionmechanisms of action

mechanisms of action

Melatonin has been shown to exert antinociceptive

and antiallodynic actions in a variety of experimental

models in animals.

(20)

Induction of pain involves the release

of several pro-inflammatory mediators like cytokines and

the activation of a number of neurotransmitter receptor

sites present in both the spinal cord and brain. The

mechanisms that melatonin may act in pain are control

the release of pro-inflammatory mediators; inhibit the

activation of receptors involved in pain perception present

at spinal cord; inhibit receptor activation in brain regions

involved in pain perception and promote sleep that can

be extremely effective for controlling/inhibiting pain

perception.

The available evidence demonstrates that melatonin

seems to have a action in the opioid system and a

modulatory effect on the circadian rhythm of nociception.

Yousaf, in a review

(21)

of the use of melatonin in peri-

operative setting, reports anxiolytic and analgesic

properties. Melatonin premedication is effective in

ameliorating perioperative anxiety in adults. Compared

with midazolam, melatonin has similar anxiolytic efficacy

but less psychomotor impairment and fewer side effects.

The elderly population has been shown to be refractory

to the hypnotic and anxiolytic effects of melatonin.

(22)

The

clinical impact of melatonin on pain need to more studied

and the evidence regarding its potential analgesic effects

in the perioperative setting is inconsistent and limited.

Melatonin premedication was associated with an analgesic

Headache Medicine, v.3, n.2, p.61-69, Apr./May/Jun. 2012 63

MELATONIN IN HEADACHE DISORDERS

effect in the studies with pain as a primary outcome,

whereas the lack of analgesic effect was observed in

studies with pain as a secondary outcome.

(23-25)

It seems

that high doses of melatonin are required to produce major

analgesic effects.

(20)

The antinociceptive and antiallodynic

properties of melatonin have a perspective in future studies

in patients that suffer from pain due to inflammation,

occurring during headache, cancer patients, neuropathic

pain and fibromyalgia. It may be useful in patients with

comorbidities like anxiety that is frequently associated with

headache disorders.

is known to be important in the pathophysiology of

migraine. Finally, melatonin inhibits the synthesis of

prostaglandin E

, which has been identified as one of

many substances that can lead to sterile perivascular

inflammation (neurogenic inflammation) that activates the

trigeminovascular nociceptive afferents.

otential therapeutic use of melatonin inotential therapeutic use of melatonin in

otential therapeutic use of melatonin in

headache disordersheadache disorders

headache disorders

Melatonin has been implicated in the treatment of

different types of headaches (Table 2).

MELATONIN AND HEADACHES

Melatonin indeed demonstrates several actions within

the central nervous system (SNC), which may account for

its putative analgesic role in headache.

(26)

(Table 1).

First, melatonin potentiates the inhibitory action of

GABA on SNC and several GABAergic drugs have been

used successfully in the prophylaxis of migraine, such as

topiramate, divalproex and gabapentin.Thus, reduced

concentrations of melatonin might lower the activation

threshold of pain circuits normally inhibited by GABAergic

transmission. Second, because melatonin modulates the

entry of calcium into cells, a reduction in melatonin might

alter the tone or vasoreactivity of cerebral blood vessels.

Furthermore, melatonin receptors have been identified on

cerebral arteries and melatonin has also been shown to

modulate 5-HT2 receptors on cerebral arteries.

Antagonism at this 5-HT receptor is exploited by drugs

used to prevent migraine and CH. Additionally, a

melatonin-driven modulation of 5HT2 receptors was

suggested, similar to drugs used for migraine prophylaxis,

such as flunarizine, methysergide and beta-blockers.

(27)

Melatonin modulates different serotonin receptors which

MIGRAINE

The literature of headache and melatonin is

convergent point to low levels of this hormone in patients

with migraine,

(28-29)

menstrual migraine,

(30-31)

chronic

migraine

(32)

and cluster headache.

(33-38)

Claustrat et al.

(28)

were the first to demonstrate lower

plasma melatonin levels in samples from migraine patients

compared with controls. Migraine patients without

depression had lower levels than controls, but migraineurs

with superimposed depression exhibited the greatest

melatonin deficiency. Murialdo et al.

(31)

also found nocturnal

urinary melatonin to be significantly decreased throughout

the ovarian cycle of migraine patients without aura

compared with controls. Melatonin excretion was further

decreased when patients suffered a migraine attack.

Brun et al.

(30)

studied urinary melatonin in women with

migraine without aura attacks associated with menses and

controls. Melatonin levels throughout the cycle were

significantly lower in the migraine patients than in controls.

In the control group, melatonin excretion increased

significantly from the follicular to the luteal phase, whereas

no difference was observed in the migraine group.

64 Headache Medicine, v.3, n.2, p.61-69, Apr./May/Jun. 2012

Peres et al.

(32)

studied plasma melatonin nocturnal

profile in chronic migraine patients and controls. Lowered

melatonin levels in patients with insomnia were observed

compared with those without insomnia, and a phase delay

in the melatonin peak in patients versus controls.

Masruha et al.

(39)

were the first to demonstrate

reduction in melatonin levels during attacks in episodic

and chronic migraine. The study assessed 6-sulpha-

toxymelatonin (aMT6s) levels in a large consecutive series

of patients with migraine, comparing with controls. A total

of 220 subjects were evaluated (146 had migraine and

74 were control subjects). aMT6s urinary samples were

measured with quantitative ELISA technique. Among

patients with migraine, 53% presented pain on the day of

the urine samples collection. Their urinary aMT6s

concentration was significantly lower than in the urine of

patients without pain. There was no significant difference

in the aMT6s concentration of patients with migraine

without pain on the day of their urine samples collection.

AMT6s levels were even lower in patients with chronic

migraine and in the presence of a migraine attack. It was

also observed that the higher is the frequency of migraine

attacks, lower levels of aMT6s. These are also strongly

correlated, inversely, with levels of depression, anxiety,

fatigue, diagnosis of excessive daytime sleepiness and

the number of points of fibromyalgia.

(40)

CHRONIC MIGRAINE

The role of the hypothalamus in the pathophysiology

of chronic migraine (CM) was first studied by Peres el al.

(32)

in a experiment to explore the hypothalamic-tubero-

infundibular system (prolactin, growth hormone), the

hypothalamic hypophyseal-adrenal axis (cortisol), and

pineal gland function (melatonin) in CM. A total of 338

blood samples (13/patient) from 17 patients with CM

and nine (age and sex matched) healthy volunteers were

taken. Melatonin, prolactin, growth hormone, and cortisol

concentrations were determined every hour for 12 hours.

The study showed an abnormal pattern of hypothalamic

hormonal secretion in CM. Forty-seven per cent of patients

with CM had a significant phase delay in the melatonin

peak, and half had insomnia. Melatonin concentrations,

peak secretion, and AUCs were significantly lower in

patients with CM who had insomnia than in controls and

patients with CM without insomnia. In conclusion, they

found a decreased nocturnal prolactin peak, a increased

cortisol concentrations, a delayed nocturnal melatonin

peak in patients with CM, and lower melatonin

concentrations in patients with CM with insomnia. It

supports the report of Nagtegaal et al.

(41)

that showed a

phase delay in the nocturnal melatonin peak in patients

with delayed sleep phase syndrome and associated

headaches. They had a great improvement of both

symptoms after treatment with 5 mg melatonin.

reatment of migrainereatment of migraine

reatment of migraine

Claustrat et al.

(29)

reported six patients with status

migranous which were treated with infusion of 20 mg of

melatonin. Four patients have a headache relief in the

morning after night melatonin infusion and the other two

patients reported an improvement after the third night of

infusion, and three patients reported a decrease in intensity

during the migraine attacks.

Nagtegaal et al.

(41)

reported the case of a 54-year-

old man who suffered from disabling migraine attacks

without aura, twice a week. After starting melatonin

treatment, only three migraine attacks were reported in

12 months.

In an open study carried out by Peres et al.

(42)

the use

of 3 mg of melatonin was effective in the preventive

treatment of migraine. Of the 34 patients who were

evaluated, 78.1% showed clinical response, defined as a

reduction greater than 50% of the frequency of attacks.

The complete response, i.e. a reduction of 100% of

seizures, was observed in 25% of patients. The frequency

of headache, duration, intensity and analgesic

consumption decreased significantly (p <0.001) in the

first month of treatment in relation to the baseline period.

Miano et al.

(43)

designed a 3-month open label trial

of melatonin prophylaxis in children with primary headache.

After a one month baseline period patients received

preventive therapy with melatonin (3 mg) administered

orally at bedtime for three months without receiving

preventive drugs. A total of 22 children were enrolled and

13 subjects had migraine without aura, one male had

migraine with aura. On assessment at the completion of

the trial, 14 of the 21 subjects reported that the headache

attacks had decreased by more than 50% with respect to

baseline, and 4 reported having no headache attacks. In

7 of the 21 children the frequency of headache attacks

remained unchanged from baseline (three with migraine

without aura and four with chronic tension-type headache).

None of the patients reported an increased number of

attacks during the trial. One subject dropped out because

of excessive daytime sleepiness.

Side effects have been reported in association with

the ingestion of melatonin but are not serious. Physiologic

GONÇALVES AL, RIBEIRO RT, PERES MF

Headache Medicine, v.3, n.2, p.61-69, Apr./May/Jun. 2012 65

effects of the hormone (hypothermia, increased sleepiness,

decreased alertness, and possibly reproductive effects),

that are dose-dependent, have not yet been properly

evaluated in individuals that use large doses of melatonin

for prolonged periods of time.

TENSION-TYPE HEADACHE

In 1998, Nagtegaal et al.

(41)

reported three women

(aged 14, 14, and 23) suffering from chronic tension-type

headache (CTTH) in a total of 30 patients with delayed

sleep phase syndrome which were treat with 5 mg

melatonin. After treatment with melatonin their headache

disappeared within two weeks.

In a trial of melatonin prophylaxis in children, Miano

et al.

(43)

treated eight patients with CTTH in total of 22

children with primary headache. After a one month baseline

period without receiving preventive drugs, all children

received a 3-month course of melatonin (3 mg)

administered orally, at bedtime. The study lasted four

months: during the first month (baseline period) patients

received no preventive therapy for recurrent headache and

for the next three months received therapy with pure

melatonin (3 mg) administered orally at bedtime. From

the total of eight patients four are males. Headache attacks

had decreased, by more than 50%, in four patients, and

none reported a complete remission of headache.

CLUSTER HEADACHE

The circadian rhythmicity of CH has oriented the

studies toward the hypothalamus. The suprachiasmatic

nucleus (SCN) is the main control center of the biological

clock, which receives retinal information on luminosity and

projects it to the pineal gland where melatonin needs to

be produced in a circadian rhythm to act satisfactorily.

(44)

During the symptomatic phase of CH, the melatonin

production is reduced until its nocturnal peak

disappears,

(35)

thus altering biological rhythms and

decreasing its additional analgesic effect related to

gabaergic reinforcement,

(33)

calcium modulation

(26)

and

prostaglandin synthesis inhibition.

(45)

In 1984, Chazot et al.

(35)

detected a decrease in

nocturnal melatonin secretion and abolished melatonin

rhythm in CH patients. Waldenlind et al.

(37)

also showed

lowered nocturnal melatonin levels during cluster periods

than remissions and found that women had higher

melatonin levels than men throughout the year.

(36)

Smokers

had lower levels than non-smoking cluster headache

patients. Leone et al.

(34)

observed melatonin and cortisol

peaks significantly correlated in controls but not in cluster

headache patients, indicating a chronobiological disorder

in these patients. Blau and Engel

(46)

observed that 75 of

200 CH patients have a increase in body temperature

from exercise, and hot bath or elevated environmental

temperature may trigger cluster headache attacks. This

finding can be explained by a decrease in melatonin

secretion caused by temperature increase.

(47)

Melatonin has been implicated in the treatment of

cluster headache. There is one study Class II RCT on

melatonin for cluster prevention.

(33)

This is a double-blind,

placebo-controlled, parallel-group trial. The RCT (20

people; 18 with episodic cluster headache; two with chronic

cluster headache) compared oral melatonin 10 mg daily

versus placebo for two weeks. In comparison to the run-in

period, there was a reduction in daily headache frequency

in the melatonin group (p < 0.03), but not the placebo

group. Two patients with chronic cluster headache did not

respond to melatonin therapy. Adverse events were not

reported.

Peres and Rozen

(48)

described two chronic CH patients

who responded to melatonin (9 mg at bedtime). Melatonin

prevented nocturnal cluster attacks and also daytime attacks.

Nagtegaal et al.

(41)

reported one patient with delayed sleep

phase syndrome in association with episodic CH in whom

both disorders improved after melatonin treatment. There

are a few trials to evaluate melatonin in prevention of CH

and it was considered Level C for the prevention of CH.

(49)

INDOMETHACIN-RESPONSIVE HEADACHE

SYNDROMES

Melatonin has a chemical structure similar to that of

indomethacin and thi fact has led researchers to use

melatonin in the treatment of indomethacin-responsive

headache.

Primary stabbing headachePrimary stabbing headache

Primary stabbing headache

Rozen

(50)

reported three patients with primary stabbing

headache (PSH) with a positive response to indomethacin

that were administered melatonin to assess its effectiveness.

The three patients were given different dosages of

melatonin (3, 9 and 12 mg, respectively). All the patients

became asymptomatic and remained so throughout a 2-

to 4-month follow-up. Melatonin appears to be an

effective alternative treatment for PSH. Melatonin has a

clearly more favorable side-effect profile than

indomethacin. Rozen recommended to start with a bedtime

MELATONIN IN HEADACHE DISORDERS

66 Headache Medicine, v.3, n.2, p.61-69, Apr./May/Jun. 2012

dose of 3 mg and then to increase the dose by 3 mg

every four nights until pain relief is obtained, setting 24 mg

as the upper dose limit. However, in most cases, no

treatment is necessary given that PSH has a natural course

of spontaneous fluctuations, with only 14% of patients

experiencing persistent symptoms.

(51)

Hypnic headacheHypnic headache

Hypnic headache

Hypnic headache (HH) or primary sleep-related

headache is a rare primary headache disorder that mainly

affects elderly people. It was first described by Raskin, in

1988,

(52)

and 174 cases have been reported in the literature

so far.

(27)

The exact pathophysiological mechanisms of

HH have not yet been elucidated. It has been postulated

that HH may be the result of a chronobiological disorder,

serotonin, and melatonin dysregulation or a disturbance

of rapid eye movement (REM) sleep. In most of the patients

with HH who had polysomnographic studies, attacks were

associated with REM sleep,

(53-57)

however, non-REM related

HHs have also been reported.

Many patients reported a good response to

indomethacin, but some could not tolerate it. Caffeine

and melatonin treatments did not yield robust evidence to

recommend their use as single preventive agents.

Nevertheless, their association with lithium or indomethacin

seems to produce an additional therapeutic efficacy.

Lithium indirectly increases the level of melatonin

(58-60)

and

may thus affect the pathophysiology of HH.

Domitrz describes a case of HH, which were effectively

treated with flunarizine and melatonin (3 mg) in a 45-

year-old woman.

(61)

Dodick

(54)

describe a 68-year-old woman presented

with a 6-year history of nocturnal headaches that awaken

her from sleep. Treatment with melatonin (3 mg) at bedtime

was begun, and headache severity decreased from

moderate to mild and duration decreased to 15 to 20

minutes. The dose was increased to 6 mg, which rendered

her headache-free over a 4-month period.

Ghiotto et al.

(62)

report two cases of HH that improve

after treatment with melatonin.

Melatonin seems to be effective in a daily dose 3-5 mg

and in association with caffeine or another drug for

prophylaxis of HH. Melatonin was effective in four of 174

cases, in a recent review; thus, more studies are necessary

to evaluate your efficacy in HH.

(27,63)

Hemicrania continuaHemicrania continua

Hemicrania continua

In a few reports melatonin was shown to be effective

for HC. Spears

(64)

reported a case of hemicrania continua

in which attacks were successfully eliminated while taking

melatonin (7 mg) at bedtime after the patient was no

longer able to tolerate indomethacin due to gastrointestinal

side effects. Rozen

(65)

also reported an improvement in

the hemicrania continua after treatment with melatonin.

HEADACHES AND PINEAL CYSTS

Pineal cysts are benign lesions found in up to 2.6%

of adults. Asymptomatic pineal cysts are usually an

incidental neuroimaging finding.

Peres et al. described five cases of primary headaches

associated with pineal cysts and suggested that pineal

cysts could be related to headache disorders not because

of compression but abnormal secretion of the pineal

hormone melatonin.

(66)

Seifert et al. studied 51 pineal cysts

patients compared with 51 controls. Pineal cyst patients

had 2-fold more headaches than controls (51% vs

25%).The most common diagnosis in pineal cysts patients

was migraine in 26%, including 14% with migraine with

aura. One patient had hemicrania continua. The authors

suggest pineal cysts may be related to headaches,

particularly migraine. Interestingly, cyst diameter was not

different in patients with headache as compared with those

without headache. This finding supports the idea of Peres

et al.

(66)

that melatonin dysfunction may be the main

mechanism related to the headache. Melatonin has been

linked extensively to headache disorders with experimental

and clinical evidence.

(33,39,42,67,68)

Unfortunately, to date,

no measures of melatonin secretion have been performed

in pineal cysts patients. Small, asymptomatic pineal cysts

require no therapy. If they become symptomatic from

hydrocephalus, surgical options can be considered. The

patient with a headache disorder and a pineal cyst may

be treated preventively with melatonin starting with 3 mg

at bedtime and increasing to 15 mg.

(67)

MELATONIN, HEADACHE AND MEDICINAL

PLANTS

Melatonin have been found in several plants of

medicinal value in species like feverfew (Tanacetum

parthenium), St John's wort (Hypericum perforatum) and

huang-qin (Scutellaria baicalensis).

(69-71)

Feverfew has been

used in migraine treatment but sufficient scientific evidence

of efficacy has not been established to date.

(72,73)

Angelicae

Dahurica combined with Scutellaria baicalensis has been

widely used as herb-pairs in traditional Chinese medicine

to treat migraine headache. The interplay between

GONÇALVES AL, RIBEIRO RT, PERES MF

Headache Medicine, v.3, n.2, p.61-69, Apr./May/Jun. 2012 67

melatonin and these other reportedly potent compounds

may be a promising field of future research.

Melatonin agonistsMelatonin agonists

Melatonin agonists

Melatonin and melatoninergic agonists may also be

important in migraine comorbidity.

(67)

Insomnia in

headache patients is the most likely associated condition

in migraine to respond to melatonin therapy. Ramelteon

(Rozeren®), a selective melatonin 1 or 2 receptor agonist

can also be used for treatment of insomnia in migraine

patients and have a profile with few side effects comparing

with hypnotics drugs.

Agomelatine is a novel antidepressant and a

melatonin agonist, a MT1 and MT2 receptor-site. It has

been approved for major depression in Brazil.

Although no controlled studies with large samples

have been published, two randomized clinical trials

controlled with placebo for migraine prevention are

registered in clinicaltrials.org, one with melatonin and other

with ramelteon.

In Brazil there is no approval of Brazilian Health

Survillance Agency (ANVISA) for the use of melatonin as

a vitamin, as is in the United States and most of developed

countries, we totally agree with that. Brazilian law enables

public advertisement when a compound is registered as

a vitamin and this is not desirable for melatonin with the

current health assistance access for the general population.

In contrast, melatonin as a natural substance found in the

human body cannot be applied for a patent, it is cheap,

therefore no pharmaceutical company has financial

interest in the application of melatonin as a medication.

Important to notice that melatonin is not a banned drug,

and not prohibited in Brazil, it is only not registered as a

vitamin or a medication, as many other compounds,

including vitamins and not yet approved medication for

oncology treatments, the patient has the right to take it

and receive the best treatment option, and the physician

has the right to prescribe the best treatment option for his

or her patient. We hope in the near future melatonin could

be better delivered to patients with the regulatory issues

resolved.

CONCLUSION

Melatonin plays a significant role in the patho-

physiology of headaches. Melatonin can also be a good

option in the treatment of primary headaches, not only

those with nocturnal occurrence but also migraine and

other headaches. In the presence of insomnia or circadian

rhythm disturbance melatonin may also be helpful.

However more randomized clinical trials should be done

in order to give more evidence for melatonin prescription

in our current practice (see take home messages).

MELATONIN IN HEADACHE DISORDERS

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MELATONIN IN HEADACHE DISORDERS

Correspondence

André Leite GonçalvesAndré Leite Gonçalves

André Leite Gonçalves

Rua Itália, 438

13070-292 – Campinas, SP, Brazil

goncalvesnp@yahoo.com.br

Reveived: 5/10/2012

Accepted: 7/5/2012