According to the Global Burden of Disease 2016 project, migraine ranks first for the age group of 15 to 49 years while it ranks second for all ages, measured as Years Lived with Disability (YLD).1 An insightful GBD study focusing on migraine reveals that there are 1.04 billion migraine patients worldwide and together they suffer from 45.1 million years lived with disability.2 Interestingly, migraine ranks high in all countries in the world and, contrary to beliefs, is not a typical western lifestyle disease. It is listed in the top five most debilitating diseases in every country (except for one in which it takes the sixth place). Migraine ranks equally high in developing countries, even though diseases such as malaria and anaemia are widespread in the developing world. The GBD-migraine study has found that at the cross-country level, there is no significant relationship between the prevalence of migraine and socio-economic status. The socio-economic development of a country “is not a major determinant of the size of the headache burden”, the authors conclude (p. 971).2
The causes of the debilitating chronic disease are still largely unknown. In addition, there is no effective treatment yet. As a consequence, migraine patients often suffer for years if not decades, which explains the high ranking in terms of disability. Studies into possible causes, comorbidities, and treatments are largely limited to clinical studies (RCTs and cohort studies) and health surveys. There are no systematic cross-country analyses available with country-level data of risk factors for migraine. Clinical studies suggest three categories of candidates for modifiable risk factors: metabolic factors (including obesity and insulin resistance), mental health factors (including depression, anxiety, and insomnia), and hormone factors (oestrogen, which may be influenced by industrial food and certain chemicals in the environment; and cortisol, a key stress hormone).3–8 Of all these modifiable risk factors, chronic stress is increasingly mentioned as a key mechanism in the development and chronification of migraine.9
A few small cohort studies have shown statistically significant relationships between migraine and external stress factors, in particular work-related stress10,11 and stress from civil war, terrorism, and combat.12–14 Why is migraine the number one chronic disease among those of working age in developed countries, where work-related stress is ubiquitous? And why is migraine the number one chronic disease in developing countries suffering from conflict or civic unrest or large refugee inflows, such as Afghanistan, Syria, Venezuela, Colombia, Jordan, Iraq, Lebanon and Palestine? In this article, I will explore the extent to which external stress factors are related to migraine at the cross-country level. The results should be taken with much caution – they are exploratory in character. The purpose of the present study is not to establish causality, but to complement findings from clinical research and country-level survey studies. The results suggest that future research on migraine and stress may be advised to take external stressors, at the societal level, into account.
Although the ultimate cause of migraine is still unknown, the neurophysiology of migraine has been described in much detail over the past decade. Migraine is a neurological disease with a cascade of effects in the brain, in which the HPA-axis (Hypothalamic-Pituitary-Adrenal axis) and the trigeminal nerve (with one of the branches behind the eyes, where migraine headache is often located) play a key role.15–18 Genetic research shows more and more genes that are related to migraine, while the fact that some patients develop migraine late in their lives whereas others report an end to the attacks suggests that epigenetic factors may play a role too.19
The HPA-axis appears to play a crucial role not only in the stress response but also in migraine, through the hypothalamus, which is responsible for regulating the autonomic and central nervous system as well as some metabolic processes (for example the regulation of glucose and insulin). Indeed, just before a migraine attack, patients often grave sweets while during the attack most patients feel nauseous. The HPA-axis is the key mechanism of the body’s response to acute stress, which may be caused by any stressor, consciously (an explosion or threat of dismissal) or unconsciously (feeling unsafe or work deadlines). But when the number of stressors becomes too high or a single stressor occurs with a high frequency, stress may become chronic. In that case, the HPA-axis is overactive and the body does not have sufficient time to recover and to bring cortisol, blood pressure, glucose, oestrogen, pulse, and breathing back to normal values.20–22 In that case, stress researchers refer argue that the brain fails to regulate the tress response adequately which is referred to as allostatic overload.22
Allostatic overload is visible in the brain. Neuroimages of individuals suffering from chronic stress show structural and functional changes in the amygdala, hippocampus and prefrontal cortex.22 Over the past decade, allostatic overload has also been related to migraine, not only from migraine to stress, but more importantly, from stress to migraine, which suggests a possible causal path.7,15,23 The brains of migraine patients appear to be highly sensitive, or hyperexcitable, in particular the hypothalamus, amygdala, and prefrontal cortex showing similar structural and functional changes as in the brains of those suffering from chronic stress.18,24 As the authors of a review study conclude, “being a migraineur means having subtle differences in brain structure and function even outside of attacks. (p. 559)25” This implies, the authors, continue, that migraineurs are particularly susceptible to environmental changes, which includes the work environment and the political context, which may lead “to inappropriate processing or interpretation of stressful information. (p. 593)25” Therefore, Bruce McEwen, one of the first stress researchers, emphasizes that our environments need to change if we want to reduce sustained stress and its effect on various diseases. He refers to policies that help to increase people’s “healthspan” rather than their “lifespan”, by “providing opportunities for individuals to experience better working and living environments. (p. 23)24”
The modern flexible work context as well as civic unrest and conflict with subsequent insecurity and refugee flows are clearly external stressors for large populations. They may, therefore, have an aggregate effect on the prevalence of migraine as well as on the severity of it, expressed together in YLD. But there are no studies available that have explored possible relationships between the prevalence or severity of migraine on the one hand and such external stressors in society on the other hand. There is a clear need for cross-country studies into these relationships. A recent editorial in Neurology concludes that various external factors “can affect the threshold for migraines, including stressful life events. (p. 53)26” Researchers have pointed in particular at work-related stress in the western world, related to an individualist, competitive work culture in ever more flexible and insecure labour markets, with continued outsourcing of low skilled work and job replacement by modern technology.27 For the developing world, basic insecurity of life is likely to be a source of chronic stress, related to civil war, violent conflict, weak states, or large refugee flows due to crises in neighbouring countries.26,28 In the absence of systematic, cross-country research, some researchers have developed hypotheses about migraine as a maladaptive response to life in stressful environments, such as today’s globalized, flexible, and complex societies.29
Combining the clinical research of migraine as a neurological maladaptive stress response with the findings from the GBD-migraine study showing the high ranking of migraine in all Western societies as well as in developing countries suffering from conflict, I suggest a very preliminary hypothesis a relationship between society-wide stressors on the one hand and migraine YLD on the other hand.