Attention Deficit Hyperactivity Disorder and Risk of Migraine

In This Article

Abstract and Introduction

Abstract

Objective: This study explored the risk of migraine in children, adolescents, and young adults with attention deficit hyperactivity disorder (ADHD) and its association with ADHD medications.

Background: The prevalence of migraine peaks between the ages of 35 and 39 years. Recent studies have reported a positive association between ADHD and migraine.

Methods: This longitudinal case-cohort study was conducted using data from the Taiwan National Health Insurance Database. Between 2001 and 2009, we enrolled 81,441 participants with ADHD and a 1:1-matched control cohort for age, sex, and physical and psychiatric comorbidities. All participants had no diagnosis of migraine before enrollment and were followed up to the end of 2011. We examined the risk of newly diagnosed migraine among patients with ADHD and matched controls after adjusting for demographics and physical/psychiatric comorbidities.

Results: Patients with ADHD had a higher incidence of migraine than those in the control group (462/81441 [0.6%] vs. 212/81441 [0.3%] patients, p < 0.001). After adjusting for potential confounders, the hazard ratio (HR) was 1.92 (95% CI, 1.64–2.34) for migraine in patients with ADHD versus controls. The subgroup analyses stratified by age showed the HRs were 2.01 (95% CI, 1.63–2.49), 1.94 (95% CI, 1.35–2.79), and 1.31 (95% CI, 0.58–2.98) for children (<12 years old), adolescents (12–17), and young adults (18–29), respectively, versus controls. When stratified by sex, the HR was 1.97 (95% CI, 1.58–2.46) for men and 1.94 (95% CI, 1.44–2.62) for women versus controls. The cumulative daily dose of ADHD medications was not associated with the risk of migraine.

Conclusion: Children and adolescents with ADHD were associated with an increased risk of migraine compared with matched controls. The increased risk was not observed in young adults with ADHD. Further studies are required to examine the mechanisms between migraine and ADHD.

Introduction

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with main symptoms of inattention, hyperactivity, and impulsivity.^[1] A previous meta-analysis of 175 eligible studies revealed that ADHD affected 7.2% of children and adolescents worldwide.^[2] A nationwide population-based study in Taiwan reported a 1.24 prevalence rate of ADHD in the population aged younger than 18 years old^[3] Children with ADHD have been associated with a higher risk of psychiatric comorbidities (e.g., mood and substance use disorders)^[4] and physical illness (e.g., epilepsy and asthma)^[5] than the controls without ADHD.

Migraine is one of the most common primary headaches in children and adolescents, with an estimated prevalence of 10.4%.^[6] The prevalence differs among races and is 15.4% in non-Hispanic White, 10.7% in Asian, and 15.7% in Black populations.^[7] Children with migraine are prone to miss daily tasks and have impairments in school performance.^[8,9] Moreover, migraine influences quality of life, mental health, and social function.^[10–12] Previous studies have reported a positive association between ADHD and migraine.^[13–16] Several plausible mechanisms were proposed to explain this positive association, including the involvement of sleep disorders, dopaminergic dysfunction, GABAergic dysfunction, dysfunctional brain iron metabolism, and shared genetic factors.^[17–20]

However, previous studies had several limitations regarding the significant association between ADHD and migraine, including relatively small sample sizes,^[13,16] cross-sectional designs,^[13,14,16] diagnostic methods (e.g., self-reported questionnaire or medication being used as a proxy for diagnoses),^[14,15] or no examination for the influence of ADHD medications.^[13,14] Furthermore, the prevalence of ADHD and migraine varies across countries and races.^[13–16] We conducted this nationwide population-based longitudinal study to investigate the association between ADHD and migraine in children, adolescents, and young adults in Taiwan. We hypothesized that the risk of migraine was higher in children, adolescents, and young adults with ADHD than those without.

Table 1. Demographic data and incidence of migraine among patients with ADHD and controls
	Patients with ADHD (n = 81,441)	Controls (n = 81,441)	p-value
Age at enrollment (years, SD, n, %)	9.0 (4.1)	9.0 (4.1)	0.684
Sex (%)			>0.999
Male	58,461 (71.8)	58,461 (71.8)
Female	22,980 (28.2)	22,980 (28.2)
ADHD medications (n, %)
<30 cDDD	38,796 (47.6)
30–364 cDDD	28,919 (35.5)
≥365 cDDD	13,726 (16.9)
Methylphenidate (n, %)
<30 cDDD	39,185 (48.1)
30–364 cDDD	28,813 (35.4)
≥365 cDDD	13,443 (16.5)
Atomoxetine (n, %)
<30 cDDD	79,468 (97.6)
30–364 cDDD	1842 (2.3)
≥365 cDDD	131 (0.2)
Incidence of migraine (n, %)	462 (0.6)	212 (0.3)	<0.001
Age at migraine diagnosis (years, SD)	14.0 (5.2)	15.20 (5. 5)	0.005
Duration between enrollment and migraine diagnosis (years, SD)	3.7 (2.7)	5.3 (2.6)	<0.001
Psychiatric comorbidities (n, %)
Disruptive behavior disorders	7902 (9.7)	152 (0.2)	<0.001
Alcohol use disorders	344 (0.4)	157 (0.2)	<0.001
Substance use disorders	650 (0.8)	215 (0.3)	<0.001
Depressive disorders	5526 (6.8)	437 (0.5)	<0.001
Bipolar disorders	1262 (1.5)	65 (0.1)	<0.001
Physical comorbidities (n, %)
Cerebrovascular diseases	449 (0.6)	449 (0.6)	>0.999
CNS infection	412 (0.5)	412 (0.5)	>0.999
Traumatic brain injury	8144 (10.0)	8144 (10.0)	>0.999
Epilepsy	2252 (2.8)	2252 (2.8)	>0.999
Level of urbanization			<0.001
1 (most urbanized)	15,152 (18.6)	22,904 (28.1)
2	24,853 (30.5)	24,936 (30.6)
3	6871 (8.4)	14,754 (18.1)
4	5937 (7.0)	11,480 (14.1)
5 (most rural)	28,627 (35.2)	7367 (9.0)

Abbreviations: ADHD, attention-deficit hyperactivity disorder; cDDD, cumulative defined daily dose; CNS, central nervous system; SD, standard deviation.

Table 2. Cox regression analysis of the risk of migraine among patients with ADHD and controls ^a
	Children (<12 years)	Adolescents (12–17 years)	Young adults (18–29 years)	Males	Females	Total
	HR (95% CI)	HR (95% CI)	HR (95% CI)	HR (95% CI)	HR (95% CI)	HR (95% CI)
ADHD
Absence	1 (ref.)	1 (ref.)	1 (ref.)	1 (ref.)	1 (ref.)	1 (ref.)
Presence	2.01 (1.63–2.49)	1.94 (1.35–2.79)	1.31 (0.58–2.98)	1.97 (1.58–2.46)	1.94 (1.44–2.62)	1.92 (1.64–2.34)

Note: Bold type indicates statistical significance.
Abbreviations: ADHD, attention-deficit hyperactivity disorder; CI, confidence interval; HR, hazard ratio.
^aAdjusted for demographic data and psychiatric and physical comorbidities.

Table 3. ADHD medications and the risk of migraine among patients with ADHD ^a
	Total	Subanalyses for risky subgroups
	Total	With any physical comorbidity	With any psychiatric comorbidity
	HR (95% CI)	HR (95% CI)	HR (95% CI)
ADHD medications
<30 cDDD	1 (ref.)	1 (ref.)	1 (ref.)
30–364 cDDD	1.03 (0.84–1.26)	0.79 (0.52–1.18)	0.91 (0.61–1.34)
≥365 cDDD	0.96 (0.74–1.25)	0.99 (0.61–1.61)	1.09 (0.69–1.72)
Methylphenidate
<30 cDDD	1 (ref.)	1 (ref.)	1 (ref.)
30–364 cDDD	1.03 (0.84–1.26)	0.81 (0.54–1.21)	0.90 (0.61–1.33)
≥365 cDDD	0.95 (0.73–1.24)	0.99 (0.61–1.61)	1.07 (0.67–1.69)
Atomoxetine
<30 cDDD	1 (ref.)	1 (ref.)	1 (ref.)
30–364 cDDD	1.66 (0.99–2.79)	2.04 (0.89–4.68)	1.46 (0.59–3.60)
≥365 cDDD	1.22 (0.170–8.7)	2.60 (0.360–18.8)	2.62 (0.360–18.9)

Abbreviations: ADHD, attention-deficit hyperactivity disorder; CI, confidence interval; cDDD, cumulative defined daily dose; HR, hazard ratio.
^aAdjusted for demographic data, psychiatric and physical comorbidities, and medications.