Stress as a migraine trigger: clinical evidence and pathophysiological insights – A narrative review

IntroductionMigraine shows a significantly higher prevalence in women, especially during reproductive age when menstrual-related hormonal fluctuations represent the most common migraine trigger. Indeed, over 50% of patients report a higher occurrence of migraine attacks during the perimenstrual window. Menstrual migraine attacks are consistently referred to as more disabling, less responsive to symptomatic treatments, longer in duration, and more prone to relapse than non-menstrual migraine attacks. Evidence strongly suggests that estrogen fluctuations are involved in migraine attacks worsening during the perimenstrual window through several mechanisms directly or indirectly involving the CGRP pathway. We aimed to evaluate whether mAbs blocking CGRP-ligand or receptor (CGRP-mAbs) could represent an effective and safe preventive treatment for menstrual migraine attacks in patients with menstrual-related migraine (MRM) with previous treatment failures.MethodsForty patients with MRM with at least three previous treatment failures received monthly CGRP-mAbs. At the baseline and after six CGRP-mAbs administrations, patients underwent to extensive interviews to assess frequency, duration, intensity, and responsiveness to painkiller intake of migraine attacks occurring during the perimenstrual window.ResultsAfter six administrations of CGRP-mAbs we observed a reduction of median menstrual migraine frequency (from 5 to 2 days per month), pain intensity (from 8/10 to 6/10), and attacks duration (from 24 to 8 h) (p < 0.001). Nevertheless, a significant increase in the percentage of responding to migraine painkillers was observed from 42.5% at baseline to 95% at T1 (p < 0.001).ConclusionsCGRP-mAbs could represent a safe and effective preventive therapeutic strategy able to reduce the disabling burden of menstrual migraine attack frequency, duration, intensity, and significantly improve the response to painkillers. These findings could be related to and further indirectly prove the greater influence of CGRP-mediated mechanisms in the pathophysiology of menstrual migraine attacks.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40122-021-00273-w.

Individuals with migraine frequently report that their attacks may be precipitated by “triggers.” In one recent survey of 200 consecutive migraine patients referred to our headache center, over 90% identified at least one migraine attack trigger; those triggers most commonly cited were physical or emotional stress (77%), menses (72% of actively cycling females), exposure to bright or flickering light (65%), and various odors (61%). Before we explore the more specific aspects of migraine triggers, some important general issues deserve mention: No single entity, however “classic” (eg, red wine, chocolate, “stress”), acts as a trigger for all migraineurs. In the individual migraineur, rarely does a trigger consistently provoke an attack. As corollary to no. 2, simultaneous exposure to 2 or more triggers may be required to provoke an attack (see below). What serves as a trigger may also serve as a treatment (eg, caffeine). Current theory holds that the clinical symptomatology we define as “migraine” reflects a relatively hypersensitive brain, with that hypersensitivity likely to be genetic in origin. The migrainous brain appears inherently sensitive to changes in the individual's “internal” or “external” environment; examples of internal change include the abrupt decline in estrogen levels occurring with menses, sudden stress (or, paradoxically, release from stress), or a change in one's usual sleep pattern (eg, oversleeping on the weekend or vacation), whereas external changes commonly cited as triggers include weather changes, ingestion of alcohol, or exposure to bright or flickering light. Following exposure to a sufficient trigger, the genetically primed migrainous brain – cocked and ready – acutely responds by initiating a cascade of clinical and electrical events that clinically are expressed as “migraine”: headache, often accompanied by nausea and sensitivity to light and sound. Again, no single trigger – however potent – is common for all migraineurs, and an established trigger rarely triggers a migraine attack each and every time in the affected individual. Furthermore, when attacks are triggered, they may involve a spectrum of migraine symptoms that extends from no headache whatsoever (ie, aura only) to a veritable pit of physical and emotional misery. For example, ingestion of red wine at times may induce you to suffer a migraine, but if you maintain a passionate devotion to red wine, because the wine/attack association may not be invariable and because the attacks you do experience consequent to indulging your passion may involve only minimal headache . . . you well might choose to play your cards and take your chances. Or perhaps not if that glass of savory rioja is to be followed immediately by a sweet dessert; if that combination invariably produces annoying or even debilitating migrainous symptoms, it's best to leave well enough alone. Along the same line, female migraineurs may find that ingestion of red wine invariably produces migraine only when the wine is drunk in association with another common migraine trigger: menses. As noted previously, over two-thirds of our actively cycling clinic patients report menstrual aggravation of their migraine. That what has proven to be a trigger at other points within the menstrual cycle may serve as a more consistent and potent trigger during menses is not surprising. A word about caffeine. Finding that caffeine may trigger an attack – or learning of this potential risk from a physician, friend, or other source – a migraineur may take pains to eliminate caffeine use entirely . . . and recoil in horror when it's suggested that whatever oral medication is being used for acute migraine treatment be taken with a caffeinated beverage. In reality, while caffeine can trigger migraine in some individuals, and although caffeine overuse can cause migraine progressively to worsen, caffeine may prove a surprisingly effective ally in treating acute migraine. During migraine attacks the stomach's characteristic motility may stall, and oral medications thus helplessly may linger in that organ . . . unable to progress down into the small intestine where they could be absorbed into the bloodstream and exert their therapeutic effect. Caffeine can assist in restoring the stomach's motility, and beyond simply promoting absorption of oral medications caffeine may itself exert a more direct therapeutic effect on the migraine process. Not by coincidence is caffeine a component of so many of the preparations available for acute headache treatment, both over-the-counter and prescription (eg, Excedrin, Goody powders, Esgic, Fioricet, Fiorinal, Cafergot). Finally, what about elimination diets? Such diets have both their diehard advocates and cold-eyed skeptics. Bottom line: (1) there are virtually no scientific data available to support an extremist position for or against such diets; (2) through their own life experiences, most migraineurs have identified what for them are clear triggers, dietary or otherwise, and have learned to avoid those dietary components that frequently provoke attacks; (3) to maintain regular eating habits – and specifically to avoid skipping meals – is likely to be of more benefit in controlling migraine than any specific diet; and (4) adopting a migraine “elimination diet” that is inherently healthful (eg, diets “Mediterranean” in composition) makes good sense whether it helps reduce migraine or not.

Migraine is a neurological disorder that is characterized by severe headaches and temporary motor and sensory disturbances. Migraine triggers are internal or external factors that can increase the likelihood of a migraine attack. Some individuals with migraine associate their attacks with the consumption of certain types of food, but no have been conducted in Iceland. The aim of the study was to estimate the proportion of individuals with migraine in Iceland who associate their symptoms with consuming certain types of food. An electronic questionnaire was submitted to two groups (≥18 years old), members of the Icelandic Facebook group 'Migreni' (n=395 and to patients being treated by a neurologist (n=108), with the question if they thought certain foods could trigger migraine attacks. A total of 503 opened the survey (19.6% in the Facebook group and 65% managed by a neurologist). Response options were never/rarely, sometimes, often, or always. Other questions included types of migraine, medication use and background. Out of 466 participants, 354 individuals (76%) claimed that food often or always triggered their migraine. The proportion was higher in the Facebook group than in the neurologist group (78% vs. 66%, p=0.007). Red wine and skipping meals (hunger) were the most common food-related triggers, reported as triggers often or always by >50%. Other common food triggers included white wine, liquorice, and smoked meat; they were reported as triggers by 20-50% of participants. Food seems to be a common migraine trigger, and the main food-related triggers were similar to those reported in other studies. However, previous studies have not shown liquorice as a common food trigger for migraines, and smoked meat was found to be a more common trigger than seen in other studies.

Blau theorized that migraine triggers are exposures that in higher amounts would damage the brain. The recent discovery that the TRPA1 ion channel transduces oxidative stress and triggers neurogenic inflammation suggests that oxidative stress may be the common denominator underlying migraine triggers. The aim of this review is to present and discuss the available literature on the capacity of common migraine triggers to generate oxidative stress in the brain. A Medline search was conducted crossing the terms "oxidative stress" and "brain" with "alcohol," "dehydration," "water deprivation," "monosodium glutamate," "aspartame," "tyramine," "phenylethylamine," "dietary nitrates," "nitrosamines," "noise," "weather," "air pollutants," "hypoglycemia," "hypoxia," "infection," "estrogen," "circadian," "sleep deprivation," "information processing," "psychosocial stress," or "nitroglycerin and tolerance." "Flavonoids" was crossed with "prooxidant." The reference lists of the resulting articles were examined for further relevant studies. The focus was on empirical studies, in vitro and of animals, of individual triggers, indicating whether and/or by what mechanism they can generate oxidative stress. In all cases except pericranial pain, common migraine triggers are capable of generating oxidative stress. Depending on the trigger, mechanisms include a high rate of energy production by the mitochondria, toxicity or altered membrane properties of the mitochondria, calcium overload and excitotoxicity, neuroinflammation and activation of microglia, and activation of neuronal nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. For some triggers, oxidants also arise as a byproduct of monoamine oxidase or cytochrome P450 processing, or from uncoupling of nitric oxide synthase. Oxidative stress is a plausible unifying principle behind the types of migraine triggers encountered in clinical practice. The possible implications for prevention and for understanding the nature of the migraine attack are discussed.

A wide variety of triggers prompt attacks in episodic migraine. Although experimental triggers such as glyceryl trinitrate reliably produce migraine, natural triggers are much less predictable and vary in importance between individuals. This review describes the most common triggers in episodic migraine and provides strategies for managing them in clinical practice. Multiple migraine attack triggers have been established based on patient surveys, diary studies, and clinical trials. Stress, menstrual cycle changes, weather changes, sleep disturbances, alcohol, and other foods are among the most common factors mentioned. Clinical studies have verified that fasting, premenstrual periods in women, "letdown" after stress, and most likely low barometric pressures are migraine triggers. Premonitory symptoms such as neck pain, fatigue, and sensitivity to lights, sounds, or odors may mimic triggers. Multiple studies clearly demonstrate triggers in episodic migraine, often related to change in homeostasis or environment. Many common migraine triggers are not easily modifiable, and avoiding triggers may not be realistic. Healthy lifestyle choices such as exercise, adequate sleep, stress management, and eating regularly may prevent triggers and transformation to chronic migraine over time.

Several biochemical, pharmacological, neurophysiological and experimental data suggest a possible role of gamma-aminobutyric acid (GABA) in the pathogenesis of migraine. We investigated the possible association of the most common single nucleotide polymorphisms (SNPs) in the GABA receptor alpha4 (GABRA4), epsilon (GABRE), and theta (GABRQ) genes with the risk for migraine. A TaqMan-based qPCR assay designed to detect the most common SNPs in the GABRA4 (rs2229940), GABRE (rs1139916), and GABRQ (rs3810651) was performed in 197 migraine patients and 394 age- and gender-matched controls. The possible influence of gender, age at onset of migraine, positive family history of migraine, presence or absence of aura, and triggering of migraine by ethanol on the frequency of the genotypes was also studied. The frequency of GABRE rs1139916AA genotype was significantly lower in the migraine group only in the female gender, but the differences did not reach statistical significance after correction for multiple comparisons. The mean±SD age at onset of migraine was significantly lower in patients with GABRQ rs3810651AA as compared with the other two genotypes. Positive family history of migraine and presence or absence of aura did not influence the frequencies of the genotypes of the three SNPs studied. Triggering of migraine by ethanol was significantly less frequent in patients with GABRA4 rs2229940GG and more frequent in patients with GABRQ 3810651TT genotype, but the differences lost statistical significance after correction for multiple comparisons. GABRQ rs3810651 could play a role in the modification of age at onset of migraine.

ObjectiveTo assess whether alcohol intake is associated with the onset of migraine attacks up to 2 days after consumption in individuals with episodic migraine (EM).BackgroundAlthough alcohol has long been suspected to be a common migraine trigger, studies have been inconclusive in proving this association.MethodsThis was an observational prospective cohort study among individuals with migraine who registered to use a digital health platform for headache. Eligible individuals were aged ≥18 years with EM who consumed alcohol and had tracked their headache symptoms and alcohol intake for ≥90 days. People who did not drink any alcohol were excluded. The association of alcohol intake (“Yes/No”) and of the number of alcoholic beverages in the 2 days preceding a migraine attack was assessed accounting for the presence of migraine on day‐2 and its interaction with alcohol intake on day‐2, and further adjusted for sex, age, and average weekly alcohol intake.ResultsData on 487 individuals reporting 5913 migraine attacks and a total of 40,165 diary days were included in the analysis. Presence of migraine on day‐2 and its interaction with alcohol intake on day‐2 were not significant and removed from the model. At the population level, alcohol intake on day‐2 was associated with a lower probability of migraine attack (OR [95% CI] = 0.75 [0.68, 0.82]; event rate 1006/4679, 21.5%), while the effect of alcohol intake on day‐1 was not significant (OR [95% CI] = 1.01 [0.91, 1.11]; event rate 1163/4679, 24.9%) after adjusting for sex, age, and average weekly alcohol intake. Similar results were obtained with the number of beverages as exposure.ConclusionsIn this English‐speaking cohort of individuals with EM who identified themselves as mostly low‐dose alcohol consumers, there was no significant effect on the probability of a migraine attack in the 24 h following consumption, and a slightly lower likelihood of a migraine attack from 24 to 48 h following use.

The prodrome or premonitory phase is the initial phase of a migraine attack, and it is considered as a symptomatic phase in which prodromal symptoms may occur. There is evidence that attacks start 24-48 hours before the headache phase. Individuals with migraine also report several potential triggers for their attacks, which may be mistaken for premonitory symptoms and hinder migraine research. This review aims to summarize published studies that describe contributions to understanding the fine difference between prodromal/premonitory symptoms and triggers, give insights for research, and propose a way forward to study these phenomena. We finally aim to formulate a theory to unify migraine triggers and prodromal symptoms. For this purpose, a comprehensive narrative review of the published literature on clinical, neurophysiological and imaging evidence on migraine prodromal symptoms and triggers was conducted using the PubMed database. Brain activity and network connectivity changes occur during the prodromal phase. These changes give rise to prodromal/premonitory symptoms in some individuals, which may be falsely interpreted as triggers at the same time as representing the early manifestation of the beginning of the attack. By contrast, certain migraine triggers, such as stress, hormone changes or sleep deprivation, acting as a catalyst in reducing the migraine threshold, might facilitate these changes and increase the chances of a migraine attack. Migraine triggers and prodromal/premonitory symptoms can be confused and have an intertwined relationship with the hypothalamus as the central hub for integrating external and internal body signals. Differentiating migraine triggers and prodromal symptoms is crucial for shedding light on migraine pathophysiology and improve migraine management.

BackgroundMigraine is a disabling primary headache disorder often associated with triggers. Diet‐related triggers are a common cause of migraine and certain diets have been reported to decrease the frequency of migraine attacks if dietary triggers or patterns are adjusted.ObjectiveThe systematic literature review was conducted to qualitatively summarize evidence from the published literature regarding the role of diet patterns, diet‐related triggers, and diet interventions in people with migraine.MethodsA literature search was carried out on diet patterns, diet‐related triggers, and diet interventions used to treat and/or prevent migraine attacks, using an a priori protocol. MEDLINE and EMBASE databases were searched to identify studies assessing the effect of diet, food, and nutrition in people with migraine aged ≥18 years. Only primary literature sources (randomized controlled trials or observational studies) were included and searches were conducted from January 2000 to March 2019. The NICE checklist was used to assess the quality of the included studies of randomized controlled trials and the Downs and Black checklist was used for the assessment of observational studies.ResultsA total of 43 studies were included in this review, of which 11 assessed diet patterns, 12 assessed diet interventions, and 20 assessed diet‐related triggers. The overall quality of evidence was low, as most of the (68%) studies assessing diet patterns and diet‐related triggers were cross‐sectional studies or patient surveys. The studies regarding diet interventions assessed a variety of diets, such as ketogenic diet, elimination diets, and low‐fat diets. Alcohol and caffeine uses were the most common diet patterns and diet‐related triggers associated with increased frequency of migraine attacks. Most of the diet interventions, such as low‐fat and elimination diets, were related to a decrease in the frequency of migraine attacks.ConclusionsThere is limited high‐quality randomized controlled trial data on diet patterns or diet‐related triggers. A few small randomized controlled trials have assessed diet interventions in preventing migraine attacks without strong results. Although many patients already reported avoiding personal diet‐related triggers in their migraine management, high‐quality research is needed to confirm the effect of diet in people with migraine.

BackgroundSport as a migraine trigger has been reported, but extensive information on these triggered attacks and the patients experiencing these attacks is lacking. Goal of this study was to investigate the lifetime prevalence of exercise triggered migraine attacks in migraine patients and if patients with exercise triggered attacks experience specific prodromal or ictal migraine symptoms.Methods103 consecutive migraine patients seen during their first visit at a Dutch headache clinic were administered an interview during their first visit to the outpatient headache clinic in which they were asked about their normal life migraine characteristics and if exercise had ever triggered a migraine attack within 48 hours after stopping exercise. Those reporting exercise triggered migraine attacks, were asked if these migraine attacks were typical or atypical compared to their normal life attacks and which kind of exercise in particular could provoke migraine attacks.ResultsAmong migraineurs lifetime prevalence of exercise-triggered migraine attacks was 38%, regardless of migraine type (with or without aura) or gender. Neck pain as the initial migraine symptom during normal life migraine attacks, was more frequent in those experiencing exercise-triggered migraine attacks. More than half of the patients reporting exercise-triggered migraine attacks abandoned the offending sport due to migraine. As our study population was drawn from a headache clinic, result can not be generalized to the general population.ConclusionsLife time prevalence of exercise-triggered migraine attacks was high. Those experiencing exercise-triggered migraine attacks, more frequently had neck pain as initial migraine symptom during normal life attacks.

Migraine is comorbid with restless legs syndrome (RLS). However, the temporal association between these two episodic disorders remains elusive. The current study investigated the temporal relationship between migraine and RLS attacks. Migraine patients with RLS were recruited from a headache clinic. Patients with symptomatic RLS, RLS mimics, daily headaches, or daily RLS attacks were excluded. The patients recorded their headaches and RLS attacks for two weeks in a diary. The severity of each headache or RLS attack was rated on a four-point (0-3) Likert scale. Logit-normal, random-effects models were employed to estimate the odds ratios (ORs) for the temporal association between migraine and RLS attacks. Thirty migraine patients with RLS (28 F/2 M, mean age 35.5 ± 9.0 years) completed the study. On the basis of 420 daily diary records, migraine attacks were associated with subsequent RLS attacks occurring on the same and next nights (OR = 6.94, 95% confidence interval (CI) = 4.39-11.0 and OR = 3.00, CI = 1.92-4.68; both ITALIC! p < 0.001). RLS attacks were associated with subsequent migraine attacks only on Day 1 (OR = 1.97 (CI = 1.3-2.98; ITALIC! p = 0.01). Overall, the frequencies of migraine and RLS attacks in two weeks were correlated (Spearman's correlation = 0.56, ITALIC! p = 0.001). Our study results showed a bidirectional triggering association between migraine and RLS attacks. The association was stronger and lasted longer for migraine triggering subsequent RLS than that for vice versa.

It is reported in some individual patients that vestibular stimuli can trigger migraine attacks. This study used a case-control design to examine systematically the hypothesis that vertigo induced by vestibular stimulation (rotation/caloric testing) can act as a specific migraine trigger. A total of 123 new patients attending neuro-otology or neurology clinics were studied with questionnaires and physician interview to ascertain migraine history according to International Headache Society criteria. A total of 79 who underwent rotation/caloric vestibular testing (test group) were compared with 44 control patients in whom no such testing was carried out (control group). The principal outcome measure was the occurrence of a migraine attack within 24 hours of exposure to vestibular stimulation. Of those participants with a past history of migraines, 19/39 (49%) of the test group experienced a migraine in the study time window, compared with 1/21 (5%) of the control group. Binary logistic regression analysis confirmed that vestibular testing was associated (p < 0.05) with migraine attacks. The results indicate that induced vertigo can act as a migraine trigger, a finding with implications for the diagnosis of patients with episodic vertigo and migraine headache. While such patients may well have basilar migraine or migrainous vertigo, alternatively, another disorder causing episodic vertigo (e.g., benign paroxysmal positional vertigo or Ménière disease) may be triggering migraine headaches.

MIGRAINE PATHOPHYSIOLOGY

Many factors trigger migraine attacks. Weather is often reported to be one of the most common migraine triggers. However, there is little scientific evidence about the underlying mechanisms and causes. In our pilot study, we used smartphone apps and a web form to collect around 4,700 migraine messages in Germany between June 2011 and February 2012. Taking interdiurnal temperature changes as an indicator for changes in the prevailing meteorological conditions, our analyses were focused on the relationship between temperature changes and the frequency of occurrence of migraine attacks. Linear trends were fitted to the total number of migraine messages with respect to temperature changes. Statistical and systematic errors were estimated. Both increases and decreases in temperature lead to a significant increase in the number of migraine messages. A temperature increase (decrease) of 5 °C resulted in an increase of 19 ± 7 % (24 ± 8 %) in the number of migraine messages.

Migraine is a type of headache with recurring attacks of unilateral pulsating pain of high intensity. It is accompanied by photophobia, phonophobia and nausea and/or vomiting. Migraine treatment is very complex because often it is not possible to apply only one medicine that will relieve the pain for a long period of time. Aim of this work is to investigate the most common problems of patients with migraine and the impact of patient education on their quality of life. The method of systematic presentation of the research of other researchers was applied. The databases Scindeks, Hrcak, Google schoolar, Scielo, BMJ were searched. According to the results of numerous studies, the most common migraine triggers are alcohol, smells, emotional disturbances, stress, fatigue, lack of sleep and hormonal changes. The most pronounced problems of migraine patients are moderate to severe pain, throbbing pain, sensitivity to light, sensitivity to sounds, nausea and vomiting during a migraine attack. The reviewed studies show that education (about migraine, triggers, headache attacks, therapy, self-care) for patients with migraine is very useful for improving their health and quality of life. Health care of migraine patients should be based on individual problems and care needs because only in this way can better control of headaches and greater functionality of patients be encouraged. Care, therapy and education help prevent migraine attacks and improve quality of life.