Association of Gastrointestinal Functional Disorders and Migraine Headache: a Population Base Study.

BACKGROUND Migraine is one of the prevalent headaches. Many of patients with migraine, complain of gastrointestinal symptoms. There is limited studies on relation of gastrointestinal symptoms and migraine headache at population level. METHODS In this population-based study, 1038 subjects older than 15 year from a rural area in Fars province, south of Iran. were investigated for functional gastrointestinal disorders. By cluster random sampling, 160 of these persons invited to receive endoscopy along with histopathology samples of upper gastrointestinal tract. Data were analyzed using Pearson chi-square and Fisher exact. RESULTS Mean age of participations were 34.3 years with female to male of 3:1. The prevalence of migraine, irritable bowel syndrome (IBS), reflux, and dyspepsia were 24.6%, 17.7%, 17.4%, and 32.1%, respectively. There were significant relationship between migraine and functional gastrointestinal diseases (odds ratio of association for migraine with IBS, reflux, and dyspepsia were 3.43, 1.68, and 1.68 with p-value < 0.001 for all). In endoscopic findings, only presence of hiatal hernia was associated significantly with migraine (p = 0.011). No histopathologic findings in antral or duodenal biopsies were associated with migraine. CONCLUSION In this population based study we found significant association between migraines and gastrointestinal functional disorders including IBS, reflux and dyspepsia. This may have implication in better management of patients with migraine headache.

INTRODUCTION

Migraine is a disabling chronic headache defined according to the International Classification of Headache Disorders as “recurrent, moderate to severe headache attacks lasting 4-72 h with associated features including nausea and/or vomiting”.[1] Migraine is one of the most prevalent medical disorders worldwide specially in out patients departments [2] and is considered as a major cause of the global burden of disease.[2-3]

Migraine is a multifactorial disease; with significant role for environmental and genetic factors.[4] Many co morbidities including psychiatric, cardiovascular and pulmonary disorders have been reported in patients suffering from migraine.[5-6]

There are limited number of studies on association of migraine and functional gastrointestinal disorders (FGD) but most of them have some bias and a few number of these studies are truly population based.[6-9] This association might be related to gastrointestinal side effects of analgesics or other drugs used in the management of migraine.[10] Although few studies suggested Helicobacter pylori infection as a pathogenic factor for migraine,[11]but other studies have not observed correlation between Helicobacter pylori infection and migraine.[12-13]

Considering the contradictory findings in previous studies, this study was designed to investigate the prevalence and association between migraine and FGD including IBS, reflux, and dyspepsia in a population-based study in Fars, southern Iran.

MATERIALS AND METHODS

This cross-sectional population-based study was conducted in two phases in a Baladeha village near Kazerun west of Fars province, Iran. Its population was 1848 subjects at the time of study of whom 1118 persons were older than 15 years. In first phase, all persons older than 15 years were invited to participate in a medical interview. Of them 1038 (92.8%) joined in by coming to health care center in this region. A Three-dimensional questionnaire was completed by physicians’ interview. First dimension was on demographic characteristics of the participants (such as gender, age, family size, literacy level, and marital status). The second dimension of questionnaire included questions on presence of migraine headache symptoms based on the latest criteria of International Headache Society.[14] The third dimension contained questions on gastrointestinal functional disorders symptoms according to Rome III criteria.[15] We used backward and forward method to translate these two questionnaires into Persian version until all difference and discrepancies were corrected. These questionnaires were validated by the study group in interviewing 50 persons in the same village. A standard medical history and physical examination was also done for all participants by the same physicians.

Those individuals who had any chronic disease including diabetes mellitus, hypertension, any cardiovascular disease, osteoarthritis, neurological disorders, documented organic gastrointestinal diseases, and recipients of treatment for migraine headache were excluded based on medical history and physical examination by the medical team consistent of four physicians.

In the second phase participants were classified into four groups based on the presence of migraine symptoms and FGD; 1) individuals with migraine and gastrointestinal symptoms 2) individual with migraine and without gastrointestinal symptoms 3) individuals without migraine but with gastrointestinal symptoms 4) individuals without migraine and gastrointestinal symptoms. For each group, 40 individuals were selected randomly based on numbers and were invited for upper gastrointestinal tract endoscopy after overnight fasting. Those with any type of heart or pulmonary diseases were excluded from invitation for endoscopy. Before endoscopy informed consent was acquired from all precipitants. Endoscopy was done by a gastroenterologist who did not know the participants’ category. In endoscopy, all parts of the upper gastrointestinal tract were examined. Two biopsies from antrum, gastric body and the first and second part of the duodenum were taken in all of endoscopies using standard biopsy forceps. Any suspected lesions were also biopsied. Samples were reviewed by a pathologist who was also blind to the subjects’ categories and the endoscopy findings.

Statistical analysis

Data were analyzed by SPSS software version 20 (SPSS, Chicago, IL, USA). Statistical analyses were performed using Chi-square test (Fisher’s exact test) and independent-samples t-test (or Mann Withney U). P-value of < 0.05 was considered statistically significant.

Ethics

The project was approved by the ethical committee of the Shiraz University of Medical Sciences.

RESULTS

1038 individuals older than 15 years participated in this study. Of these 755 (56.4% female) fulfilled the inclusion criteria. The levels of educations’ participants were 38.9% (404) illiterate, 40.3% (418) less than middle school, 17.6% (183) less than high school, and 3.2% (33) had university education. 61% (638) lived in a family with more than 5 people. The mean age of participants was 34.3 years (range: 15 to 87 years).

Table 1 demonstrates the prevalence and association of migraine and FGD with demographic variables in our study. 24.6% (246) participants by international headache society criteria had migraine. Migraine was more prevalent in female (p < 0.001), those with lower education (p < 0.001), and married (p = 0.004). Prevalence of IBS, reflux, and dyspepsia were 17.7% (184), 17.4% (178), and 32.1% (328) based on Rome III criteria respectively. Prevalence of different types of dyspepsia was 63.4% (208) epigastric pain syndrome (EPS), 24% (79) post parandial distress (PDS) syndrome, 12.6% (41) unspecific.

Table 1

Demographic characteristics and the relationship these with considered diseases

Variables		N. Mi	Mi	P	N.IBS	IBS	P	N.Ref	Ref	P	N.Su	Su	p
Gender	Male	329	54	<0.001	334	61	0.131	320	67	0.945	285	102	0.002
		(43.6)	(22)		(39.1)	(33.2)		(37.9)	(37.6)		(41.1)	(31.1)
	Female	426	192		520	123		524	111		409	226
		(56.4)	(78)		(60.9)	(66.8)		(62.1)	(62.4)		(58.9)	(68.9)
Age groups	15-24	272	69	0.329	284	67	0.604	298	50	0.189	250	98	0.061
		(36)	(28)		(33.5)	(36.4)		(35.3)	(28.1)		(36)	(29.9)
	25-34	205	76		238	56		239	50		186	103
		(27.2)	(30.9)		(27.9)	(30.4)		(28.3)	(28.1)		(26.8)	(31.4)
	35-44	117	45		136	30		137	27		102	62
		(15.5)	(18.3)		(15.9)	(16.3)		(16.2)	(15.1)		(14.7)	(18.9)
	45-54	61	20		73	12		64	19		64	19
		(8.1)	(8.1)		(8.5)	(6.5)		(7.6)	(10.7)		(9.2)	(5.8)
	55-64	71	27		86	15		76	24		64	36
		(9.4)	(11)		(15.1)	(8.2)		(9)	(13.5)		(9.2)	(11)
	=> 65	29	9		35	4		30	8		28	15
		(3.8)	(3.7)		(4.1)	(2.2)		(3.6)	(4.5)		(1.4)	(3)
Literacy	Illiterate	268	120	<0.001	334	70	0.634	311	87	0.008	262	136	0.421
		(35.5)	(48.8)		(39.1)	(38)		(36.8)	(48.9)		(37.8)	(41.5)
	Less than middle school	305	97		337	81		343	67		283	127
		(40.4)	(39.4)		(39.5)	(44)		(40.6)	(37.6)		(40.8)	(38.7)
	Less than middle school	154	25		155	28		162	19		123	58
		(20.4)	(10.2)		(18.1)	(15.2)		(19.2)	(10.7)		(17.7)	(17.7)
	Universityeducation	28	4		28	5		28	5		26	7
		(3.7)	(1.6)		(3.3)	(2.7)		(3.4)	(2.8)		(3.7)	(2.1)
Marital	Single	210	46	0.004	223	46	0.754	232	31	0.005	196	67	0.008
		(27.8)	(18.7)		(26.1)	(25)		(27.5)	(17.4)		(28.2)	(20.4)
	Married	545	200		631	138		612	147		498	291
		(72.2)	(81.3)		(73.9)	(75)		(72.5)	(82.6)		(71.8)	(79.6)
Family size	Less than 5	300	87	0.221	333	71	0.918	332	66	0.574	254	144	0.025
		(39.7)	(35.4)		(39)	(38.6)		(39.3)	(37.1)		(36.6)	(43.9)
	More than 5	455	159		521	113		512	112		440	184
		(65.3)	(64.6)		(61)	(61.4)		(70.7)	(62.9)		(63.4)	(37.1)
Total		246	755	1001	854	184	1038	844	178	1022	694	328	1022
		(24.6)	(75.4)	(100)	(82.3)	(17.7)	(100)	(82.6)	(17.4)	(100)	(67.9)	(32.1)	(100)

§ N. Mi, non Migraine; Mi, Migraine; N. IBS, non irritable bowel syndrome; IBS, irritable bowel syndrome; N. Ref, non reflux; Ref, reflux; N. Dy,

dyspepsia; Dy, dyspepsia

§ Data expressed as Number (percent)

No significant association between demographic variables and IBS, reflux were found. But dyspepsia was more prevalent in lower educated (p = 0.008), and married (p = 0.005) and in females (p = 0.002), and in those with smaller family size (p = 0.025).

Coexistence of migraine in persons with IBS was 33.3% (82), 28.5% (70) in reflux, and 41% (101) in dyspepsia. Our statistical analyses demonstrated that there were a strong significant association between migraine and these gastrointestinal diseases with odd ratio (OR) for IBS 3.43 (95% CI: 2.40 - 4.89), for Reflux 1.68 (1.19 - 2.35), for dyspepsia 1.68 (1.23 - 2.29) with P-value < 0.001. Coexistence of migraine and different types of dyspepsia was 24% (59) with EPS, 14.6% (36) with PDS, and 2.4% (6) with unspecific which were all significant statistically (p < 0.001). (Table 2)

Table 2

Relation between Migraines with gastrointestinal functional disorders studies

Gastrointestinal disorders	Mig	N. Mig	Total	OR (CI)*	P-value
IBS	82 (33.3)	96 (12.7)	178 (17.8)	3.43 (2.40-4.89)	0.001
N. IBS	164 (66.7)	659 (87.3)	823 (82.2)
Ref	70 (28.5)	154 (13.8)	174 (17.4)	1.68 (1.19-2.35)	0.001
N. Ref	176 (71.5)	651 (86.2)	827 (82.6)
Dys	101 (41)	221 (29.3)	322 (32.1)	1.68 (1.23- 2.29)	0.001
N. Dys	145 (59)	534 (70.7)	679 (67.9)

N. Mig, non Migraine; Mig, Migraine; N. IBS, non irritable bowel syndrome; IBS, irritable bowel syndrome; N. Ref, non reflux; Ref, reflux;

N. Dys, dyspepsia; Dys, dyspepsia

Data expressed as Number (percent); OR is unadjusted with (95% Confidence Interval)

Among all endoscopic findings, only hiatal hernia was statistically significant more prevalent in persons with migraine headache (p = 0.011). No pathologic finding on gastric or duodenal biopsies were associated with migraine headache. (Table 3)

Table 3

Finding pathology based on migrain

Finding Pathology	Mig	N. Mig	OR (CI)	P-value
Antrum Gastritis	49(73.1)	41(67.2)	1.32 (0.57-3.04)	0.464
Antrum Germinal Center	9(13.4)	14(23.3)	0.52 (0.18-1.43)	0.161
Antrum Atrophy	2(3.0)	4(6.5)	0.43(0.03-3.20)	0.339
Antrum Intestinal Metaplasia	9(13.5)	8(13.4)	1.02 (0.32-3.30)	0.957
Antrum Helicobacter Pylori	24(35.9)	22(36.1)	0.98 (0.45-2.17)	0.977
Body Gastritis	4(6.1)	4(6.5)	0.90 (0.16-5.09)	0.891
Body Germinal Center	1(1.5)	1(1.6)	0.90 (0.01-72.53)	0.946
Body Atrophy	1(1.5)	0(0.0)	-	0.338
Body Intestinal Metaplasia	0(0.0)	1(1.6)	-	0.292
Body Helicobacter Pylori	0(0.0)	1(1.7)	-	0.292
Duodenum Germinal Center	0(0.0)	0(0.0)	-	-
Duodenum giardiasis	3(4.5)	3(4.9)	0.90 (0.11-7.04)	0.906
Duodenum Metaplasia	10(15.0)	10(16.4)	0.89 (0.30-2.16)	0.819
Total pathology	67	61	-	-

N. Mi, non Migraine; Mi, Migraine

Data expressed as Number (percent)

Data analyzed by Pearson chi-square (Fisher exact).

DISCUSSION

This study is to our best knowledge the first population-based study to investigate the prevalence and association of migraine and gastrointestinal functional disorders in persons older than 15 years based on International Headache Society and Rome III criteria with correlation with endoscopic and pathologic findings. Using strict exclusion criteria we avoided the confounding effect of other comorbid conditions as well as the effect of use of analgesics or other drugs.

The prevalence of migraine in our study was 24.6%. A systematic review and meta-analysis from Iran showed that prevalence of migraine in adolescence and adult was 7.14% to 18.11% respectively.[16] In another systematic review and meta-analysis, it was demonstrated that migraine prevalence in children was from 5.6% to 8%.[17] Women were the dominant gender in our study group, as the prevalence of migraine is higher in females, this could explain the higher prevalence of migraine in our report.[18-19]The life style and diet pattern of our study group could also had contribution.[20]

Based on our findings, the prevalence of IBS was 17.7%. This was similar to the university-based study at shiraz university of medical sciences (16.4%).[21] In population-based studies conducted in China,[22] Pakistan,[23]and Saudi Arabia [24] the prevalence of IBS was13.25%, 28.3%, and 31.8%, respectively. Various factors such as gender age, ethnicity, diet, and physical activity can influence on IBS prevalence.[25]

With the launch of new Rome IV Diagnostic Criteria for Functional Gastrointestinal Disorders, the prevalence of IBS might be reported lower and some cases of IBS might be categorized under other titles.[26]

The prevalence of reflux was 17.4% in present study. Other population-based studies reported a prevalence of 10% to 20%.[27-28]

The prevalence of dyspepsia in our study was 32.1%. Systematic review and meta-analysis conducted by El-Serag et al. was shown that 10% to 40% of people had dyspepsia in the world which our result was being in this range.[29] Iranian studies was demonstrated that the prevalence of dyspepsia was from 2.2% to 29.9%.[30-31] Explanations for these differences may be due to the fact that some of these studies did not use Rome Diagnostic Criteria for Functional Gastrointestinal Disorders.

Our findings showed that 33.3% of IBS group had migraine headache. The same figure was reported from a population-based study in American.[32-33] This association might be related to higher prevalence of anxiety/depression in both groups and may result from the so called visceral hyperalgesia.[4,32] It is postulated that migraine patients with functional dyspepsia may have increased hypersensitivity to gastric distention and reduced tolerance to food compared to healthy people.[34]

Findings from other studies revealed that comorbid reflux in migraine patients had a range from 22%[10] to 42.6%.[5] Our result showed that this was 28.5%. Although it is unclear why reflux is increasing among migraine patients, perhaps the correct explanation might be related to the common pathology in these diseases. Gastric reflux has been reported to precipitate attack of migraine.[34] Further Autonomic nervous system (ANS) dysfunction can play an important role in the etiology of both disorders.[35-36]

Prevalence of migraine in dyspeptic patients was reported 60% (with confidence interval; 44% to 74%)[37] in our study this was 41%. As mentioned before abnormal visceral hypersensitivity may have role in both.[38-41] Furthermore, several neuropeptides are involved for both these diseases.[42-48] For instance the neuropeptide calcitonin gene-related peptide (CGRP) which is increased during migraine attacks can also cause dyspepsia.[49]

Few studies are published on prevalence of endoscopic and gastrointestinal histopathologic findings among patients with migraine.[50-52] These studies reported a high prevalence of gastritis in the antrum or gastric corpus, and duodenitis among migraine sufferers.[50-52] The main problem in these studies is not excluding patients on analgesics. In our study, the endoscopic and pathologic findings were not statistically significant between migraine and non-migraine groups except for the presence of hiatal hernia. This difference could be to our strict criteria in excluding persons on analgesic drugs.

The major strength of our study was its population based design with a large number of participants. However, it has some limitations including higher rate of participation of female subjects .The new Rome IV criteria was not available at the time of the study.

In summary, this study revealed an association between migraine and gastrointestinal functional disorders including IBS, reflux and dyspepsia. Hiatal hernia was the only abnormal endoscopic finding in patients with migraine headache. These finding may have implication in chronic management of patients with migraine.