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 Table of Contents  
Year : 2021  |  Volume : 38  |  Issue : 1  |  Page : 28-32

The effects of melatonin treatment on headache and vasomotor reactivity in patients with chronic tension-type headache

1 Department of Neurology, Faculty of Medicine, TOBB University of Economics and Technology, Ankara, Turkey
2 Department of Neurology, Gülhane Training and Research Hospital, University of Health Sciences, Ankara, Turkey
3 Department of Neurology, Liv Hospital, Ankara, Turkey

Date of Submission11-Jun-2019
Date of Decision20-Jun-2019
Date of Acceptance13-Jan-2021
Date of Web Publication26-Mar-2021

Correspondence Address:
Bilgin Öztürk
Department of Neurology, Gulhane Training and Research Hospital, Ankara
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/nsn.nsn_7_21

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Objectives: Chronic tension-type headache (TTH) is a serious disease that disrupts quality of life. In this study, the effect of prophylactic oral melatonin treatment on headache and cerebral vasomotor reactivity (VMR) was investigated in patients diagnosed with chronic TTH per the International Classification of Headache Disorders criteria. Subjects and Methods: Twenty patients with chronic TTH and 20 healthy individuals were included in the study. The patients were administered a melatonin treatment at 3 mg/day for 12 weeks. The number of monthly painful days and pain severity were recorded with the “Visual Analog Scale” before and after the treatment. Cerebral VMR measurements were performed at baseline in the control group and in patients before and after the treatment. Results: The median number of monthly painful days was 20 (15–27) before the treatment and 10 (4–18) after the treatment; the median pain severity score was 70.00 (45–80) before the treatment and 42.50 (15–75) after the treatment. The difference was statistically significant (P = 0.001). No statistically significant difference between the VMR values was observed (P > 0.05). Conclusions: Melatonin treatment was effective in reducing the pain severity and decreasing the number of monthly painful days in patients with chronic TTH but demonstrated no effect on the cerebral VMR.

Keywords: Chronic tension-type headache, melatonin, treatment, vasomotor reactivity

How to cite this article:
Eroglu E, Öztürk B, Özön A&, Koç G, Karadaş &. The effects of melatonin treatment on headache and vasomotor reactivity in patients with chronic tension-type headache. Neurol Sci Neurophysiol 2021;38:28-32

How to cite this URL:
Eroglu E, Öztürk B, Özön A&, Koç G, Karadaş &. The effects of melatonin treatment on headache and vasomotor reactivity in patients with chronic tension-type headache. Neurol Sci Neurophysiol [serial online] 2021 [cited 2023 Mar 22];38:28-32. Available from: http://www.nsnjournal.org/text.asp?2021/38/1/28/311968

  Introduction Top

Tension-type headache (TTH) is the most common headache type which is included in the primary headache classification. The prevalence of TTH in the general population is between 30%–78% in different studies.[1] It is usually a mild-moderate, bilateral, nonthrobbing, blunt, and compressive headache that does not significantly affect daily activities. The pain is bilateral in 90% of cases, and the typical region is the occipital, parietal, temporal, and frontal regions.[2]

TTHs display episodic and chronic forms. The episodic form is split into frequent and uncommon (less than one pain attack per month) types. Chronic TTH is a serious disease that decreases quality of life and increases disability.[1] While the exact mechanisms have not been elucidated, TTH is usually triggered by stress.[3] While peripheral pain mechanisms play a role in episodic TTH, it is thought that central pain mechanisms mainly play a role in chronic TTH.[1] It is believed that migraines and TTH occur using the same physiopathological process but manifest with different clinical findings. While a migraine is likely to cause pain with an important vascular component, TTH causes pain with a larger myofascial component.[2]

While it is known that TTH is directly associated with the muscle strain, its origin is thought to be more central due to the overstimulated nature of the trigeminal caudal nucleus and other structures of the central nervous system. Emotional stress, anxiety, depression, and myofascial factors that precipitate TTH cause it to be affected by the limbic system and myofascial or vascular structures. One of the most important findings of chronic TTH is increased pericranial tenderness when touched by hand that continues in the interictal period, with tenderness increasing proportionally with pain.[1]

According to diagnostic criteria for chronic TTH (the International Classification of Headache Disorders [ICHDs], 2013), headaches must occur more than 15 days per month on average for more than 3 months (≥180 days per year) and last hours to days, or with an unremitting nature. At least two of the following four characteristics must be included: bilateral location, pressing or tightening quality, mild or moderate intensity, and a lack of aggravation caused by routine physical activity such as walking or climbing stairs. More than one of the following conditions should not accompany the headache: photophobia, phonophobia, or mild nausea. Moderate-to-severe nausea or vomiting should not be present. Finally, the headache must not be better represented by other potential ICHD-3 diagnoses.[1]

Melatonin (N-acetyl-5-methoxytryptamine) is a hormone that is mainly secreted by the pineal gland cells at night, and is in the opposite direction of serotonin rhythm. The night concentrations of melatonin in the blood and cells are 3–10 times higher compared to daytime levels. Melatonin exhibits these effects through specific receptors present in the target tissues, including most of the peripheral tissues and especially the retina, brain, and hypophyseal in the body. It has been demonstrated that melatonin exhibits a significant analgesic effect via centrally weighted mechanisms along with the facilitation of GABAergic transmission. The pineal gland contains a considerable amount of opioid analgesic, opioid receptor, and opioid nerve endings so that strong opioids such as endorphin and morphine increase melatonin secretion. The analgesic effect of melatonin disappears in experimental animals from which the pineal gland has been removed. It has also been demonstrated that opioid receptor antagonists decrease the threshold of pain and eliminate the analgesic effect of melatonin. In addition, the analgesic effect of melatonin is mediated by hypophysis-induced increased endorphin secretion.[4]

Vasomotor reactivity (cerebrovascular reactivity)

Transcranial Doppler (TCD) ultrasonography is a very safe and sensitive method that is used to measure the cerebral blood flow rate from large intracranial cerebral arteries. This method can be used for the detection of the blood flow characteristics of the proximal part of the cerebral arteries, microembolus, and VMR assessment.[5] Cerebral VMR has the potential to maintain, decrease, or increase the cerebral blood flow against the changes in the perfusion pressure of cerebral arteries that occur spontaneously or pharmacologically.[6],[7] It has been demonstrated to decrease vasoconstriction caused by pharmacological agents such as serotonin and phenylephrine in diabetic rats and to cause VMR.[1]

Melatonin has an analgesic feature and is used in some neuropsychiatric diseases such as TTH, although the studies on this subject remain inadequate. It has also been observed that the number of articles investigating the effect of melatonin on cerebral VMR is very small. In this study, we investigated the effect of melatonin on chronic TTH and its effects on cerebral VMR when used in these patients.

  Subjects and Methods Top

Patients diagnosed with chronic TTH according to the 2013 ICHD criteria were included in the study. Patients older than 18 years with normal physical and neurological examination, displaying a headache for an average of 15 days or more per month for at least 3 months, and meeting the criteria for the diagnosis of chronic TTH (group TTH) were included in the study. Those with the following chronic diseases, clinical history, or current treatments were excluded from the study: hypertension, diabetes mellitus, carotid disease, cerebrovascular disease, anemia, and malignancy; cervical and cerebral surgery; antidepressant, anxiolytic, antipsychotic drugs in the last three months; or displaying a primary or secondary headache. The study protocol was approved by the local ethics committee, and written informed consent was obtained from all participants before the study (1491-716-09/1539).

Physical and neurological examinations, hemogram, and routine biochemistry examinations of all patients were performed to evaluate the exclusion criteria. Neuroimaging studies (computerized brain tomography or brain magnetic resonance imaging) were also performed in patients when necessary. According to these criteria, a total of 20 patients consisting of 14 females and 6 males with chronic TTH were included in the study. Furthermore, 20 healthy individuals (15 females and 5 males) were included in the study as the control group for VMR assessment.

Patients who were diagnosed with chronic TTH and included in the study had both pain severity and the number of painful days per month recorded using the “Visual Analog Scale” (VAS) assessment at the beginning of the study. Furthermore, the cerebral VMR measurements of bilateral middle cerebral artery (MCA) and posterior cerebral arteries (PCAs) were performed using the TCD images of the patients diagnosed with chronic TTH and the control group. Oral administration of melatonin was initiated at a dosage of 3 mg/day in the patients with chronic TTH. In the 12th week of melatonin treatment, the VMR measurements of bilateral PCA and MCAs and VAS assessment were repeated using the same method.

TCD records were taken after 10 min of relaxation in the comfortable supine position using the DWL Multi-Dop T TCD Doppler device. A 2-MHz probe was fixed to the transtemporal window. While the Doppler signals obtained from the MCAs were detected at an average depth of 50 mm from the probe placed in the temporal region, the signals obtained from the PCAs were detected at an average depth of 58 mm. The breath-holding method was used for VMR measurement in all groups. For the calculation of breath-holding indexes, the patients and the control group held their breath for 30 s three times with a 5-min interval.

Statistical analysis

Statistical analyses were performed using SPSS version 16 software. The suitability of the variables for normal distribution was examined by the Kolmogorov–Smirnov test. Descriptive analyses were performed using the mean and standard deviation for the variables that were compatible with normal distribution, and the median and minimum–maximum values for the variables that were not compatible with a normal distribution. The data that were compatible with normal distribution were compared between independent groups using the Student's t-test. The data that were not compatible with normal distribution were compared using the Mann–Whitney U-test in independent groups and using the Wilcoxon test in dependent groups. The ratios in independent groups were compared using the Chi-square test. The results with a P value below 0.05 were considered to be statistically significant.

  Results Top

The TTH patient group included 14 (70%) females and 6 (30%) males with a mean age of 35.05 ± 8.27 years. The control group included 15 (75%) females and 5 (25%) males with a mean age of 34.25 ± 8.12 years [Table 1]. No statistically significant difference was found between the control group and the TTH group in terms of gender and age (P > 0.05).
Table 1: Age and gender findings of the individuals included in the study

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In the TTH group, the median of the number of painful days in the month before the melatonin treatment was 20.00 (15.00–27.00). The median number of painful days decreased to 10.00 (4.00–18.00) after the 12-week melatonin treatment. The difference in number of painful days before and after the treatment was statistically significant (P < 0.001) [Table 2].
Table 2: Data before and after melatonin treatment

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In patients with chronic TTH, the VAS pain severity median before the treatment was 70.00 (45.00–80.00). After the 12-week melatonin treatment, the VAS pain severity median was found to be 42.50 (15.00–75.00), and this difference was statistically significant (P < 0.001) [Table 2].

The basal and final values of bilateral MCA and PCA VMR performed in the TTH group and the control group before starting melatonin treatment are presented in [Table 3]. No statistically significant difference was found between the values of bilateral MCA and PCA VMR in the control and TTH groups before or after the treatment (P > 0.05)[Table 4].
Table 3: Vasomotor reactivity basal values of the patient and control groups

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Table 4: Vasomotor reactivity data before and after melatonin treatment

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  Discussion Top

This randomized clinical trial was evaluated by a 12-week follow-up period. The use of 3 mg melatonin per day in patients with chronic TTH was found to be effective in decreasing the frequency of attacks and severity of pain. Before the treatment, the VMR values of the chronic TTH group and the control group were found to be similar. In the chronic TTH group, no change was observed in the VMR values after treatment. In recent studies, the importance of melatonin in the treatment of headaches has been emphasized, and an attempt to develop treatment strategies has been made.[8]

The use of melatonin is a promising treatment for chronic TTH. In the literature, there are several studies on the use of melatonin in the treatment of chronic TTH in adults and children.[9],[10] Bougea et al. observed a significant decrease in the frequency and severity of headaches after the oral administration of 4 mg of prophylactic melatonin per day for 6 months in 12 patients with chronic TTH.[9] In another study where eight children with chronic TTH received oral melatonin at 3 mg/day for 3 months, a >50% decrease in pain attacks occurred in four patients,[10] although no change was observed in the other four. In this study, we found a statistically significant decrease in the frequency and severity of headaches in patients with chronic TTH at the end of a 12-week program of 3 mg/day of oral melatonin, in accordance with the literature.

Melatonin plays a role in regulating the circadian rhythm, increasing sleep quality, and improving headache outcomes. Apart from these effects, melatonin has antioxidant, analgesic, and anxiolytic properties mediated by increasing the membrane stabilization, anti-inflammatory, and gamma-aminobutyric acid (GABA) signals, directing stimulating beta-endorphin release, and inhibiting the production of nitric oxide (NO).[11],[12],[13]

In chronic TTH, it has been suggested that the NO system and N-methyl D-aspartate receptors may play a role in the development of central sensitization, and that NO triggers a spontaneous headache from blood vessels, perivascular nerve endings, or brain tissue.[8] While NO synthase inhibitor decreases headache frequency and muscle spasm, NO-releasing agents may cause more headaches in patients with chronic TTH compared to healthy controls.[14] Furthermore, melatonin also presents as a free radical protector by inhibiting proinflammatory cytokines and modulating the GABA-A receptor function, and is known to exhibit antinociceptive characteristics.[15] The thrombocyte GABA levels were found to be significantly higher in patients with chronic TTH compared to migraine patients and healthy controls.[16]

Nagtegaal et al. investigated the effects of melatonin on various types of headache and their relationship with delayed sleep phase syndrome; the authors demonstrated that TTH entered complete remission in the 2nd week of 5 mg of melatonin per day treatment of three patients with chronic TTH and were included in 30 disease groups.[17] In the present study, it was observed that the patients with chronic TTH had a statistically significant decrease in their headache severity after melatonin treatment.

During a study of 21 patients with chronic TTH, a significant decrease in the number of painful days was observed in the 3rd month of evaluation of a 3 mg/day oral melatonin treatment protocol; a significant decrease was also observed in the severity of pain as evaluated by the VAS.[8] In the present study, there was a significant improvement both in the number of painful days and VAS scores of the patients with chronic TTH who received melatonin treatment.

In the literature, there are no studies on the changes in the cerebral VMR in patients with chronic TTH receiving melatonin treatment. Some publications have focused on the administration of TCD in patients with chronic TTH not receiving treatments such as topiramate or apomorphine.[7],[18] In a study where 20 patients with chronic TTH were administered TCD treatment, no significant difference was determined in terms of ultrasonic characteristics when they were compared with the control group. It was reported that there was no change in the intracerebral blood flow rates in the pathogenetic mechanism of chronic TTH.[19]

Wallasch et al. measured cerebrovascular reactivity (CVR) during the Valsalva maneuver in patients with migraine and TTH and determined an increase in the CVR for patients with migraine + TTHs compared to the healthy control group.[20] Because changes in the intracranial artery diameter play an important role in migraine pathophysiology, some studies in the literature have focused on changes in the blood flow rate and cerebral VMR of intracranial arteries in migraine patients.[21],[22] Our patients were diagnosed with chronic TTH, not migraines, and no change was determined in VMR after the 12-week melatonin treatment. This is related to the pathogenesis of chronic TTH, and while migraine headache is likely to cause pain with an important vascular component, TTH causes pain with a larger myofascial component.[2]

  Conclusions Top

The use of melatonin in chronic TTH was determined to be an effective treatment method. A decrease in the frequency and severity of pain occurred in chronic TTH patients who received melatonin. It was observed, however, that melatonin treatment did not cause cerebral VMR change. No serious side effect occurred during melatonin treatment that would result in the termination of the study. These finding suggest that melatonin treatment was an effective, reliable, and alternative option for chronic TTH patients. There is a need for randomized, double-blind, placebo-controlled, and long-term follow-up studies that include the use of melatonin at different doses and durations to exactly probe the efficiency of melatonin in the treatment of chronic TTH, including its effect on VMR.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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Nagtegaal JE, Smits MG, Swart AC, Kerkhof GA, van der Meer YG. Melatonin-responsive headache in delayed sleep phase syndrome: Preliminary observations. Headache 1998;38:303-7.  Back to cited text no. 17
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  [Table 1], [Table 2], [Table 3], [Table 4]


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