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NEUROLOGY | ORIGINAL ARTICLE

HIGH SERUM LEVEL OF CALCITONIN GENE-RELATED PEPTIDE (CGRP) AS RISK FACTOR FOR CHRONIC TENSION TYPE HEADACHE ON MEDICAL STUDENTS OF UDAYANA UNIVERSITY

I Made Oka Adnyana^∗,1, I Putu Eka Widyadharma^∗, Anak Agung Ayu Putri Laksmidewi^∗, Anna Marita Gelgel^∗and Kade Agus Sudha Naryana^∗

∗Department of Neurology, Medical Faculty of Udayana University, Sanglah General Hospital Bali, Indonesia.

ABSTRACT Background:Chronic tension-type headache is an episodic attack of headache that lasts several minutes to several days. Calcitonin gene-related peptide is an amino acid peptide that is released during headaches to the blood circulation. Numerous studies suggest that CGRP plays a role in the pathogenesis of TTH. This study aims to determine whether high serum CGRP levels are a risk factor for CTTH in students of the Medical Education Study Program at the Faculty of Medicine, Udayana University.Methods:This is a case-control study with subjects Udayana FK students aged 19-21 years. The study was conducted at the Udayana University Campus from December 2018 to March 2019. Subjects were divided into CTTH (Case) groups and groups without CTTH (Control). Serum CGRP levels were examined in each group. Data analysis using the descriptive method, bivariate with Chi-Square test to calculate the odds ratio (OR).

Results:The study used 60 subjects (30 subjects with CTTH and 30 subjects without CTTH). Subjects with a mean age of 19.77 ± 0.73 years. The normal limit for the serum CGRP level used in this study was 137.56 pmol / l. High serum CGRP increased CTTH 45 times higher than controls (95% CI 9.73-208.08; p <0.001). Conclusion:High serum CGRP levels significantly increase the CTTH incidence on Medical Students of Udayana University.

KEYWORDSCGRP, tension headache, risk factor

Introduction

Headache is the third most diagnosed neurology clinic and is the complaint most often complained by patients. One study showed that nearly 93% of its population study complained of a headache during its lifetime. From a cohort study, 76%

of women and 57% of men reported complaining of headache at least once a month [1]. Chronic tension-type headache is a

First Received: November 29, 2019 Accepted: January 09, 2020

Manuscript Associate Editor: Ivan Inkov (BG)

1Department of Neurology, Medical Faculty of Udayana University, Sanglah General Hospital Bali, Indonesia, email: [email protected]

daily headache or more frequent episodic headache that lasts several minutes to several days. Headache is bilateral, sup- presses or binds in mild or moderate quality and intensity, and pain does not increase with routine physical activity. There may be mild nausea, photophobia or phonophobia [2]. Calcitonin gene-related peptide is a 32-amino peptide acid that is localized mainly in nerve fibres C and Aδ[3]. CGRP will be released and found in the cerebral circulation, is a powerful vasodilator in the peripheral sympathetic nervous system, and is said to have a role in the inflammatory process, and it is still being debated whether CGRP is pro-inflammatory or anti-inflammatory [4].

Although the pathophysiological process is thought to be a link between CGRP and TTH, studies examining the relationship between the two are still limited. The study aimed to prove that high CGRP levels were a risk factor for CTTH in medical students.

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Table 1Basic characteristic of research subjects.

Characteristics Case (n=30) Control (n=30) Age (years ±SD) 19,77±0,73 19,77±0,73

Sex (n (%))

Male 14 (46,7) 14 (46,7)

Female 16 (53,3) 16 (53,3)

Table 2Analysis Biavariate of Calcitonin Gene-Related Peptide (CGRP) Serum level to CTTH.

Case Control OR P

n (%) n (%) (IK 95%) CGRP

serum

High 27 (90) 5 (16,7) 45 (9,73-208,08) <0.001

Normal 3 (10) 25 (83,3)

Methods

This research was conducted with a case-control design. The research subjects were selected from the students of Medical Edu- cation Study Program Faculty of Medicine, Udayana University Semester 5 and 6, aged 19-21 years. A total of 60 samples were selected by simple random sampling that met the inclusion cri- teria, divided into two groups, namely the group suffering from CTTH (case group) and the group not suffering from CTTH (control group). Serum CGRP levels were examined in each group.

Then the data were analyzed using descriptive methods, the comparative hypothesis test of two groups using the Chi-Square test and assessing the strengths carried out with the Odds Ratio.

Results

From the data obtained, the results of the basic characteristics of research subjects are as follows:

In Table 1. can be seen the basic characteristics of research subjects. Both cases and controls had a mean age of 19.77 ± 0.73 years (matching process). The number of male research subjects was 28 people (46.7%) and women as many as 32 people (53.3%).

The relationship between serum CGRP levels and CTTH were assessed using bivariate analysis. The hypothesis test used is chi-square because the data used are categorically nominal unpaired. The odds ratio (OR) with a 95% confidence interval and significance are set at a probability value p <0.05. The results of the analysis are shown in Table 2. From this study, it was found that high serum CGRP levels significantly increased the risk of experiencing CTTH 45 times compared to normal CGRP levels (95% CI 9.73-208.08; p <0.001).

Discussion

Headache is the most common symptom suffered by students.

Medical students are a vulnerable group because graduation and specialization require a large workload, namely both the- oretical and practical activities during education, lack of sleep, unhealthy lifestyles, irregular diets, and stress [5].In the patho- physiology of TTH, it is said that the process of nociception from myofascial tissue is thought to play an important role. Some

neuropeptides are thought to be involved in the occurrence of pain input from myofascial tissue and in the process of central sensitization. Calcitonin gene-related peptide (CGRP) is a neuropeptide that is widely available in the peripheral and central nervous systems. In humans, sensory afferent fibres with small blood vessels express the CGRP in cranial muscles. There is evidence of acute and chronic nociception causing changes in the release of CGRP from the sensory nerve endings and the central terminal to the dorsal horn of the spinal cord. The den- sity of CGRP fibres around the arteries also increases in muscles that experience persistent inflammation [6]. Calcitonin gene- related peptide is a 32-amino peptide acid which is localized mainly in nerve fibres C and Aδ [7]. CGRP will be released and found in the cerebral circulation, is a powerful vasodilator in the peripheral sympathetic nervous system, and is said to have a role in the inflammatory process, and it is still debated whether CGRP is pro-inflammatory or anti-inflammatory [8].

Although the pathophysiological process is thought to be a link between CGRP and TTH, studies examining the relationship between the two are still limited. In a study of 30 patients with TTH and 34 controls, CGRP levels measured from peripheral circulation in patients without headache were higher than those in controls (63 ± 5 pmol / L versus 53 ± 3 pmol / L; p = 0.06).

In patients, there was no difference in CGRP levels between ictal and interictal both in the cranial circulation (p = 0.91) and peripheral (p = 0.62). Serum CGRP levels were higher in the ex- ternal jugular vein compared to the antecubital vein on the day without headache (p = 0.03), but not on the day with headache (p = 0.82). Analysis of 8 patients with stabbing headache quality had higher interictal CGRP levels than controls (p = 0.002) whereas it is normal in 22 patients with depressed headache quality (p = 0.36) [6]. Another study, examining plasma CGRP concentrations during the interictal period in migraine and TTH patients compared with the control group, found plasma CGRP concentrations did not differ in the three groups (F = 0.78; p = 0.49). Serum CGRP concentrations also did not differ between episodic and chronic TTH groups (t = 0.32; p = 0.97) and between episodic and chronic migraine groups (1.14 compared to 0.94 ng / ml; p = 0.23) [9]. The difference in results in the two studies above due to differences in the number of subjects used. Also,

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there are differences in population. Where the population used inhomogeneous research. The selection of reagents used will also trigger differences in research results.

In chronic pain, dysfunction of the modulating system de- scending pain results in the process of decreasing pain inhibition in dorsal horn neurons. The process of central sensitization is more dominant. It is well known that the role of CGRP in this neutral sensitization is very influential. So that in chronic pain there will be an increase in CGRP levels [10].

Conclusion

Based on the results of this study, it was concluded that high serum CGRP levels had a risk factor higher than normal serum CGRP levels for the occurrence of CTTH on Medical Students of Udayana University.

Disclosure Statement

There were no financial support or relationships between the authors and any organization or professional bodies that could pose any conflict of interests.

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