The Ambiguous Role of Caffeine in Migraine Headache: From Trigger to Treatment

Abstract

Migraine is a chronic disorder, and caffeine has been linked with migraine for many years, on the one hand as a trigger, and on the other hand as a cure. As most of the population, including migraineurs, consume a considerable amount of caffeine daily, a question arises as to whether it influences their headaches. Indeed, drinking coffee before a migraine attack may not be a real headache trigger, but a consequence of premonitory symptoms, including yawning, diminished energy levels, and sleepiness that may herald a headache. Here, we aim to summarize the available evidence on the relationship between caffeine and migraines. Articles concerning this topic published up to June 2020 were retrieved by searching clinical databases, and all types of studies were included. We identified 21 studies investigating the prevalence of caffeine/caffeine withdrawal as a migraine trigger and 7 studies evaluating caffeine in acute migraine treatment. Among them, in 17 studies, caffeine/caffeine withdrawal was found to be a migraine trigger in a small percentage of participants (ranging from 2% to 30%), while all treatment studies found caffeine to be safe and effective in acute migraine treatment, mostly in combination with other analgesics. Overall, based on our review of the current literature, there is insufficient evidence to recommend caffeine cessation to all migraine patients, but it should be highlighted that caffeine overuse may lead to migraine chronification, and sudden caffeine withdrawal may trigger migraine attacks. Migraine sufferers should be aware of the amount of caffeine they consume and not exceed 200 mg daily. If they wish to continue drinking caffeinated beverages, they should keep their daily intake as consistent as possible to avoid withdrawal headache.

Full text

Nutrients 2020, 12, 2259; doi:10.3390/nu12082259 www.mdpi.com/journal/nutrients
Review
The Ambiguous Role of Caffeine in Migraine
Headache: From Trigger to Treatment
Magdalena Nowaczewska 1,*, Michał Wiciński 2 and Wojciech Kaźmierczak 3
1 Department of Otolaryngology, Head and Neck Surgery, and Laryngological Oncology, Faculty of
Medicine, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie
9, 85-090 Bydgoszcz, Poland
2 Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz,
Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland; wicinski4@wp.pl
3 Department of Sensory Organs Examination, Faculty of Health Sciences, Collegium Medicum in Bydgoszcz,
Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland; wojciech.kazmierczak@umk.pl
* Correspondence: magy_mat@by.onet.pl; Tel.: +48-52-585-4716
Received: 07 July 2020; Accepted: 26 July 2020; Published: 28 July 2020
Abstract: Migraine is a chronic disorder, and caffeine has been linked with migraine for many
years, on the one hand as a trigger, and on the other hand as a cure. As most of the population,
including migraineurs, consume a considerable amount of caffeine daily, a question arises as to
whether it influences their headaches. Indeed, drinking coffee before a migraine attack may not be
a real headache trigger, but a consequence of premonitory symptoms, including yawning,
diminished energy levels, and sleepiness that may herald a headache. Here, we aim to summarize
the available evidence on the relationship between caffeine and migraines. Articles concerning this
topic published up to June 2020 were retrieved by searching clinical databases, and all types of
studies were included. We identified 21 studies investigating the prevalence of caffeine/caffeine
withdrawal as a migraine trigger and 7 studies evaluating caffeine in acute migraine treatment.
Among them, in 17 studies, caffeine/caffeine withdrawal was found to be a migraine trigger in a
small percentage of participants (ranging from 2% to 30%), while all treatment studies found
caffeine to be safe and effective in acute migraine treatment, mostly in combination with other
analgesics. Overall, based on our review of the current literature, there is insufficient evidence to
recommend caffeine cessation to all migraine patients, but it should be highlighted that caffeine
overuse may lead to migraine chronification, and sudden caffeine withdrawal may trigger
migraine attacks. Migraine sufferers should be aware of the amount of caffeine they consume and
not exceed 200 mg daily. If they wish to continue drinking caffeinated beverages, they should keep
their daily intake as consistent as possible to avoid withdrawal headache.
Keywords: migraine; headache; caffeine; coffee; trigger; withdrawal headache; adenosine;
vasoconstriction; cerebral blood flow
1. Introduction
Migraine has emerged as a great public health concern, and the World Health Organization
(WHO) has classified it as the third most common disease worldwide, with over a billion people
estimated to suffer from it [1,2]. This type of primary headache usually presents with recurrent,
typically unilateral and pulsating attacks of severe headaches, lasting from 4 to 72 h, with
accompanying symptoms including photophobia, phonophobia, nausea, and vomiting [3]. Caffeine
has been linked with migraine for many years, on the one hand as a trigger, and on the other as a
cure [4–8]. As most of the population, including migraine sufferers, consume a considerable amount

Nutrients 2020, 12, 2259 2 of 16
of coffee and other caffeinated drinks and foods daily, a question arises as to whether it influences
their headaches. Besides, some migraine sufferers ask their doctors about dietary recommendations
regarding their intake of caffeinated beverages. They demand specific information regarding
whether they are allowed to drink coffee or should avoid it, and whether it will be beneficial for their
migraine if they stop drinking it. The aim of this review is to examine the relationship between
caffeine and migraine, and to check whether caffeine is a migraine trigger and avoiding it may be of
benefit to certain patients, and to find out if caffeine may be helpful in migraine treatment.
1.1. Caffeine
Caffeine is the most popular and widely used active food ingredient, with up to 80% of the
population consuming a caffeinated product every day [9]. One of the most popular caffeine drinks
is coffee, and many people start their day with a cup of coffee. Caffeine also occurs in tea leaves,
guarana, cocoa, chocolate, cola nuts, and wide variety of medications, dietary supplements, soft
drinks, and energy drinks [10]. As the structure of caffeine is similar to adenosine, it works through
nonselective antagonism of adenosine A1 and A2A receptors, causing their inhibition. It is important
to note that adenosine is an inhibitor of neuronal activity in the nervous system; its receptors have
been reported to be involved in antinociception, and enhancing them may lead to arousal,
concentration, and vigilance [11]. However, caffeine has no influence on dopamine release, thus has
no potential for abuse [12]. In humans, after oral intake, caffeine is rapidly and completely absorbed
(max t 30–120 min) and freely crosses the blood–brain barrier [10]. Although a main component of
coffee is caffeine, it should be pointed out that it is a complex drink including over 1000 compounds,
most of them not yet identified. Haskell-Ramsay compared the effects of regular coffee,
decaffeinated coffee, and placebo on mood and cognition, and discovered that decaffeinated coffee
also increased alertness when compared to placebo. Thus, the behavioral activity of coffee seems to
expand beyond its caffeine content, and the use of decaffeinated coffee as a placebo may be
controversial [13]. It is reported that moderate daily caffeine intake (300–400 mg, around 4–5 cups of
coffee) is safe and does not raise any health concerns (except in pregnant women and children) [14].
Nevertheless, higher doses may induce anxiety, nervousness, headache, drowsiness, nausea,
insomnia, tremor, tachycardia, and increased blood pressure [10]. Interestingly, there is evidence
that response to caffeine consumption may be genetically determined [12]. Besides, the amount of
caffeine that produces adverse effects can vary and is influenced by the person’s weight and sex, the
presence of hypertension and hepatic disease, and metabolic induction and inhibition of cytochrome
P-450 [15]. It is noteworthy that people who consume caffeine habitually have a lower risk of
experiencing the adverse effects than those who do not frequently consume caffeine [10].
1.2. Caffeine’s Influence on Health
Coffee consumption is associated with a number of health benefits in men and women. In an
umbrella review, Grosso et al. demonstrated that caffeine was associated with a decreased risk of
cancer, diabetes, cardiovascular disease and mortality, and Parkinson′s disease but an increased risk
of pregnancy loss [16]. On the other hand, coffee was linked with a rise in serum lipids and blood
pressure. Overall, they concluded that coffee (moderate daily intake) can be part of a healthful diet
[16]. A number of epidemiological studies confirmed a link between higher coffee consumption and
better performance on cognitive tests in older adults, and an inverse relationship exists between
coffee consumption and the risk of developing Parkinson′s or Alzheimer′s disease and a lower risk
of stroke. Interestingly, regular coffee consumption does not affect patients with epilepsy [17]. It is
reported that caffeine can enhance awareness, attention, and reaction time by stimulating
wakefulness, increasing concentration, and decreasing the sensation of fatigue, but also may disturb
sleep quality [14,17,18]. Moreover, caffeine in low doses (150–200 mg) can improve mood states and
decreases the risk of depression and suicide [17].

Nutrients 2020, 12, 2259 3 of 16
1.3. Caffeine and Cerebral Blood Flow
The effect of caffeine on blood flow and arteries remains controversial. On the one hand, there is
evidence that caffeine decreases the production of nitric oxide (NO, responsible for vasodilation)
from the endothelial cells, and on the other hand, a number of studies showed increased NO
production after caffeine administration [19,20]. Several studies investigated the direct effects of
caffeine on endothelial function and concluded that caffeine augmented and improved
endothelium-dependent but not endothelium-independent vasodilatation, suggesting that it has no
effect on vascular smooth muscle function [21,22]. The reason for this ambiguous effect, called by
Higashi the “coffee paradox,” may be a different action of caffeine on endothelium and smooth
muscles [21]. It is known that caffeine is an adenosine receptor antagonist. Interestingly, adenosine
via the adenosine A2A receptor stimulates the production of NO with further vasodilatation, but
contrary to this, via the adenosine A1 receptor, adenosine decreases NO release and produces
vasoconstriction. Thus, depending on caffeine binding affinity and dose, it can cause either
vasoconstriction or vasodilatation and sometimes even no change in vascular function [21]. It is
important to note that methylxanthines such as caffeine usually induce vasodilatation except in the
central nervous system, where they raise cerebrovascular resistance (CVR) and reduce cerebral
blood flow (CBF) [23]. A number of studies demonstrated that by inducing vasoconstriction, caffeine
reduces CBF in healthy people, but also in pathological conditions. Vidyasagar at al. discovered a
global 20% reduction in gray matter CBF with caffeine and tea but not decaffeinated tea, which
indicates that only caffeine change CBF. Moreover, the effect of caffeine was regionally specific.
Interestingly, none of the interventions had an effect on CVR [24]. Haanes et al. investigated the
effect of adenosine A2A receptor antagonists on the vasodilation of the middle meningeal artery.
They found that antagonists did not influence neurogenic vasodilation, but blocked the vasodilation
produced by A2A receptor agonists, suggesting that selective A2A receptor antagonists might be
useful in migraine treatment by preventing meningeal arterial dilation [25]. Another study, using
vascular information extracted from the blood-oxygen-level-dependent (BOLD) signal in functional
MRI (fMRI) showed that shorter time delays and smaller standard deviations were detected in scans
of caffeinated areas. This means that caffeine increased blood flow velocity by vasoconstriction [26].
The spatial distribution of adenosine receptors may be one reason for the region-dependent changes
in brain activity induced by caffeine, thus, the average brain metabolic rate stays unchanged.
Besides, caffeine′s effects on arteries may be region-specific [27]. Blaha et al., in a transcranial
Doppler (TCD) study, investigated the effects of caffeine on an already dilated cerebral circulation
and found a significant decrease in CBF velocity after caffeine ingestion in a normal cerebrovascular
bed as well as in peripheral vasodilatation. This means that caffeine may regulate CBF under various
pathological conditions, with possible therapeutic effects in vasoparalysis [28]. Lunt et al., using two
methods of cerebral blood flow measurement (transcranial Doppler and xenon clearance),
demonstrated that 250 mg caffeine reduced CBF by an average of 22% in healthy volunteers as well
as in patients recovering from stroke. Caffeine caused a smaller change in middle cerebral artery
(MCA) blood flow velocity than in CBF, which indicates that caffeine reduces the MCA diameter
[29]. Addicott et al. used perfusion magnetic resonance imaging to check the effect of caffeine on
CBF in chronic users of low, moderate, and high amounts in an abstained state and the normal use
(native) state. In each state, participants received either caffeine (250 mg) or placebo. It was found
that in both states, caffeine reduced CBF by an average of 27%, but in the native placebo condition,
users of high amounts of caffeine trended toward less CBF than those who consumed low and
moderate amounts. These results suggest a limited ability of the cerebrovascular adenosine system
to compensate for high amounts of daily caffeine [30]. Another TCD study examined whether
controlled caffeine cessation would produce headache and changes in CBF velocity. After 24 h of
caffeine abstinence, 10 individuals developed headache with an accompanying increase in CBF
velocity. One hour after caffeine intake, the headache resolved and CBF velocity decreased. The
study indicates a link between caffeine withdrawal, headache, and CBF [31]. Sigmon et al., in a
double-blind study, demonstrated that acute caffeine abstinence increased mean, systolic, and

Nutrients 2020, 12, 2259 4 of 16
diastolic velocity in the MCA and anterior cerebral artery (ACA) and decreased the pulsatility index
in the MCA measured by TCD [32].
1.4. Caffeine′s Effects on Pain and Non-Migraine Headache
There is evidence that caffeine may reduce pain sensation through its effects on adenosine
receptors [12]. The antinociceptive effects of caffeine may be explained by an inhibition of
cyclooxygenase activity as well as adenosine receptor antagonism. Caffeine acts not only by central
blocking of adenosine receptors, which affects pain signaling, but also by blocking peripheral
adenosine receptors on sensory afferents [12]. It was demonstrated that a 200 mg caffeine dose can
inhibit the analgesic effects of transcutaneous electrical nerve stimulation [33]. Caffeine (≥100 mg)
combined with a standard dose of analgesics led to an increased proportion of individuals with a
satisfactory level of pain relief [34]. Laska et al. found that, in combination with paracetamol or
aspirin, caffeine reduced the amount of analgesic needed to reach the same effect by approximately
40% [35]. Other clinical effects in these patients may be linked with the promotion of the absorption
of analgesics by rapid lowering of gastric pH. Nevertheless, meta-analyses of caffeine combined
with ibuprofen, paracetamol, or acetylic acid found only weak adjuvant effects in patients with
postoperative pain [34].
It has been proved that caffeine and caffeine-containing analgesics are effective in the treatment
of several types of primary and secondary headaches. For example, it is known to terminate hypnic
headache, a sleep-related headache disorder that wakes people from sleep at a consistent time [36].
Based on observational studies, the most effective acute and prophylactic treatment of this rare
disease is caffeine [37]. Another type of headache that may benefit from caffeine is post-dural
puncture headache (PDPH), the most common complication of lumbar puncture and spinal
anesthesia. A Cochrane review published in 2015 revealed that treatment with caffeine reduced
PDPH in a number of participants and decreased the need for supplementary interventions
compared to placebo [38]. This effect is probably due to increased production of cerebrospinal fluid
(CSF), as one study demonstrated that long-term consumption of caffeine induced
ventriculomegaly, and adenosine receptor signaling can regulate the production of CSF [39]. It has
been reported that caffeine withdrawal can often produce headaches. According to the International
Classification of Headache Disorders (ICHD-3), a withdrawal headache is a headache experienced
by individuals who frequently consume caffeine (>200 mg/d for >2 weeks) and suddenly stop. They
develop a headache within 24 h after their last caffeine intake, which is relieved within 1 h by
ingesting caffeine (100 mg) or resolves within 7 days after caffeine withdrawal [3]. The higher the
baseline level of caffeine ingestion, the greater the likelihood of withdrawal headache. The cause of
this type of headache is probably increased CBF due to vasoconstriction [31]. It is important to note
that caffeine withdrawal has been described as the cause of reversible cerebral vasoconstriction
syndrome in several cases of this rare sudden thunderclap headache [40,41]. Ward et al., in a
double-blind placebo-controlled trial, examined whether caffeine alone has independent analgesic
effects on non-migraine headaches, and found equivalent effects to acetaminophen [8]. According to
Mazzoni et al., overuse of caffeine was found in 36.6% of patients with chronic cluster headaches,
compared to only 6.9% of patients with episodic headaches [42]. Interestingly, patients with chronic
daily headaches were more likely to overuse caffeine before the onset of the headache, compared
with controls with episodic headaches. Nevertheless, no association was found regarding present
caffeine consumption [43]. Medication overuse headache (MOH) is a rebound headache that usually
occurs with frequent use of analgesics to relieve headaches (more than 10–15 days a month).
Kluonaitis et al. revealed that caffeine-containing combination analgesics were overused among
35.8% of patients with migraines [44]. Another study showed that combination analgesics were the
most frequently overused medications by MOH patients, and caffeine was a component of 89.9% of
these [45]. A randomized double-blind study conducted in patients with tension-type headache
revealed that treatment with ibuprofen and caffeine provided significantly greater analgesic effect
than ibuprofen alone, caffeine alone, or placebo. Notably, no analgesic effect of caffeine alone (200
mg) compared with placebo was found [46].

Nutrients 2020, 12, 2259 5 of 16
1.5. Caffeine and Migraine
1.5.1. Caffeine as Migraine Treatment: Potential Mechanism of Action 1
Although caffeine has been used for migraine headaches for many years, at the beginning its
efficiency was linked with vascular properties. As caffeine produces cerebral vasoconstriction, it was
thought that by this mechanism it may stop migraine attack. However, the role of vasodilatation in
migraines is unclear, and recent findings challenge its necessity [47]. Nowadays, it is known that
migraine is a neurological, not vascular, disorder, so the therapeutic effect of caffeine seems to be
beyond its vascular effects. It is reported that adenosine is one of the neuromodulators that
contribute to migraine pathophysiology. First of all, adenosine plasma levels increase during
migraine attacks and exogenous adenosine may start migraine headaches [48]. Besides, an adenosine
uptake inhibitor (dipyridamole) may increase the frequency of migraine attacks. Finally, as caffeine
competitively antagonizes adenosine′s effects by binding to some of the same receptors, it may be
effective in migraine treatment [36]. On the other hand, it is important to note that regular use of
caffeine-containing analgesics is associated with medication-overuse headaches. It was
demonstrated that migraine sufferers have gastric stasis not only during, but also outside of acute
migraine attacks [49]. This reduction in gastric motility slows the absorption of acute medications
and diminishes their effectiveness [50]. As caffeine increases gastric motility, this may have
important clinical implications for migraine patients, and may contribute to its effectiveness when
combined with analgesics [34]. Caffeine, by inhibiting phosphodiesterases and blocking adenosine
receptors, can potentially alter nitric oxide (NO) production. Bruce et al. demonstrated that caffeine
diminished exhaled NO, probably by adenosine receptor antagonism or by altering levels of cGMP
[19]. As NO levels increase in jugular venous plasma during a migraine attack and NO synthase
inhibitors are effective in migraine treatment, it is possible that caffeine as a biologically active
compound may decrease the frequency of migraine attacks by inhibiting NO synthase production
[51]. Recently González at al. found that regular coffee consumption may be associated with changes
in some intestinal microbiota groups [52]. As there is a relationship between migraine and the
gut–brain axis and probiotics were found to be beneficial in migraine treatment, this can be another
mechanism by which caffeine may influence migraines [53,54].
1.5.2. Caffeine as a Migraine Trigger: Potential Mechanism of Action
Trigger factors are events or exposures that increase the probability of an attack over a short
period of time [55]. The 10 most frequent migraine triggers are stress; fatigue; fasting; auditory,
visual, and olfactory triggers; hormonal triggers; sleep; weather; and alcohol [56]. Dietary triggers
are less frequent, and include chocolate, coffee, red wine, nuts, cheeses, citrus fruits, processed
meats, monosodium glutamate, and aspartame [57]. It is possible that an isolated trigger is
insufficient to precipitate a migraine attack, thus, migraine sufferers usually recognize multiple
dietary triggers [58]. Caffeine may act as a trigger in two possible ways: drinking coffee or other
caffeinated beverages may start a migraine attack, and caffeine withdrawal is an even more frequent
migraine trigger [59,60]. The prevalence of coffee as a migraine trigger in the reported literature
ranges from 6.3% to 14.5% [36]. Moreover, caffeine overuse is one of the risk factors of migraine
chronification, thus promoting the transformation of episodic migraine into its chronic form (when
headaches persist for ≥15 days/month for >3 months) [61,62]. It is important to note that caffeine
consumption was not significantly connected to medication overuse in chronic migraine patients
[63]. A question arises: What is the exact mechanism by which caffeine can induce migraine
headache? First, caffeine induces urinary loss of magnesium, probably by reducing its reabsorption
[64]. As magnesium affects neuromuscular conduction and nerve transmission and plays a beneficial
role in chronic pain conditions and migraines, caffeine, by decreasing the magnesium level, may
induce headache [65]. Dehydration is one possible migraine trigger [66]. Caffeinated coffee in higher
doses induces an acute diuretic effect, and subsequently may lead to dehydration [67]. Courturier et
al. linked weekend migraine attacks to caffeine withdrawal. In their study, patients with high daily
caffeine consumption on workdays and reduced or delayed intake on weekends (because of

Nutrients 2020, 12, 2259 6 of 16
prolonged sleep) had an increased risk of weekend headache [68]. Thus, the observed higher
frequency of migraines during weekends may be linked with caffeine withdrawal [68].
On the other hand, the methodological difficulties of investigating the influence of trigger
factors on migraine are highlighted by many authors [58]. Premonitory features are defined as
symptoms associated with an increased probability of aura or headache [55]. It is known that certain
trigger factors can overlap with corresponding premonitory symptoms; for example, food craving in
the premonitory phase may be responsible for eating chocolate or other foods, thus, they may be
misinterpreted as migraine triggers [69]. It is possible that premonitory symptoms, including
yawning, diminished energy levels, and sleepiness, may force migraineurs to drink coffee or
caffeinated beverages, leading to the wrong conclusion that they triggered a migraine, while it was
just a consequence of starting a migraine attack. On the other hand, premonitory sleepiness makes
migraineurs prone to caffeine overuse, with further migraine chronification. Interestingly, according
to Alstadhaug et al., the prodromal phase of migraine and caffeine withdrawal syndrome share the
same or similar pathophysiological pathways [4].
A question arises as to whether caffeine may induce cortical spreading depression (CSD) in
migraine aura sufferers. Yalcin at al. demonstrated that neither acute/chronic administration nor
withdrawal of caffeine affected CSD susceptibility or related cortical blood flow changes in mice.
Thus, they concluded that the influence of caffeine on headache is not linked with CSD
pathophysiology, which may explain the non-migrainous presentation of caffeine-related headache
[70].
Thus, should migraine patients strictly avoid all potential triggers, including caffeine? First of
all, trigger avoidance create frustration, which may limit the beneficial effects or make the situation
worse. Moreover, migraine is a disorder of the habituation of the CNS to sensory signals, thus, the
brain should be trained to habituate to, not avoid triggers [71]. It is reported that short exposure to a
headache trigger may increase sensitivity, while chronic exposure results in diminished sensitivity
(leading to desensitization). According to Martin et al., patients with migraines should cope with
triggers rather than avoid them [72].
If caffeine is a migraine trigger, does its cessation influence migraine attack frequency? Mikulec
et al. demonstrated that only 14% of vestibular migraine patients reported an improvement in
symptoms upon caffeine cessation [73]. Lee et al. evaluated the effect of caffeine cessation on the
acute treatment of migraine. After controlling for covariates, caffeine cessation was independently
connected with excellent efficacy of acute treatment. Indeed, 72.2% of those in the abstinence group
reported excellent efficacy of triptans compared with only 40.3% in the non-abstinence group (p =
0.002). Besides, the abstinence group trended toward a greater reduction in headache impact test-6
(HIT-6) scores [74]. On the other hand, Mostofsky et al. revealed no association between one to two
servings of caffeinated beverage intake and the odds of headaches on that day; only three or more
servings were linked with higher odds of headache [75]. As caffeine dose per serving varies by type
of drink and preparation method it may be difficult to assess the amount with increased risk. The
average caffeine content of an 8 oz cup of coffee is around 100 mg [10]. It means that migraineurs
may consume up to 200 mg caffeine without increased attacks risk.
All possible mechanisms regarding the influence of caffeine on migraine headache are
summarized in Figure 1.

Nutrients 2020, 12, 2259 7 of 16
Figure 1. Possible mechanisms by which caffeine may trigger or stop migraine attacks (based on our
literature review). Abbreviations: CBF—Cerebral blood flow, CVR—Cerebrovascular resistance,
CSF—Cerebrospinal fluid, NO—Nitric oxide, Mg—Magnesium.
2. Materials and Methods
This review includes all articles concerning the association between migraines and
caffeine/coffee published up to June 2020. The list was obtained by searching clinical databases,
including the PubMed, MEDLINE, Google Scholar, and Cochrane Library databases. Papers
regarding any connection between caffeine/coffee and migraine were identified through a literature
search. The applied terminology and keywords included “caffeine”, “coffee”, “caffeine withdrawal”,
“adenosine”, “migraine”, “headache”, “trigger factors”, “treatment”, and “pain”. Each article was
then cross-referenced to identify relevant studies. Only English language studies were eligible for
inclusion. All types of articles, including clinical trials, observational, cross-sectional, and
case-control studies, were involved and reviewed. Two independent investigators extracted data
from each article.
3. Results and Discussion
3.1. Prevalence of Caffeine as a Migraine Trigger Factor
All studies investigating the prevalence of caffeine/coffee or caffeine withdrawal as a trigger
factor in patients with migraines are summarized in Table 1.

Nutrients 2020, 12, 2259 8 of 16
Table 1. Overview of studies investigating the prevalence of caffeine/coffee as a trigger factor in
migraineurs. TTH, tension-type headache; MWA, migraine without aura; MA, migraine with aura;
EM, episodic migraine; CM, chronic migraine; TF, trigger factor.
Author (Year)
Study Design
Study Design
(Method of
Identifying
Trigger Factors)
Study Group:
Type of
Headache
(Number of
Participants)
Study
Population
Age (Years)
Coffee/Caffeine
Reported as a
Trigger Factor
(%)
Additional
Information
Beh 2019 [76]
Retrospective
cross-sectional
Retrospective chart
review
Vestibular
migraine (n =
131)
No data
11.5
Tai 2018 [77]
Prospective
cross-sectional
Comprehensive
dietary checklist
Migraine (n =
319)
Migraine
37.1 ± 14.3
Migraine 25.4
Caffeine
significantly
associated with
migraines
compared to TTH
TTH 15.1
TTH (n = 365)
TTH 46.5 ±
18.1
MWA (n = 188)
MA (n = 128)
CM (n = 91)
Taheri 2017 [78]
Prospective
observational case
series
Food diary
Migraine (n =
65)
Range
10–15
28
87% of patients
achieved complete
resolution of
headaches by
exclusion of 1–3
triggers
TTH (n = 50)
Mean 10.5
Park 2016 [79]
Prospective
cross-sectional
Smartphone
headache diary
application
Episodic
migraine (n =
62)
Mean 37.7 ±
8.6
2.4
MWA (n = 60)
MA (n = 2)
Peris 2016 [80]
Prospective
cross-sectional
Detailed 90-day
paper diary
database from
PAMINA migraine
study
Migraine (n =
326)
No data
7.7
Rist 2014 [81]
Cross-sectional
study among
participants in the
Women’s Health
Study
Semi-quantitative
food frequency
questionnaire
Non-migraine
headache (n =
5573)
Mean 53.6
Not applicable
Patients with
non-migraine
headache more
likely to have low
intake of coffee;
women who
experienced
migraine were less
likely to have low
intake of coffee
compared to those
with non-migraine
headache
Migraine (n =
7042)
MWA (n =
2972)
MA (n = 1974)
Mollaoglu 2013
[57]
Prospective
cross-sectional
Interview TF
checklist
Migraine (n =
146)
Mean 36.32
6.3
MWA (n = 73)
MA (n = 53)
Fraga 2013 [82]
Prospective
cross-sectional
Predetermined list
of trigger factors
Migraine (n =
100)
Range
10–20
Total 14
EM female 17.85
EM (n = 50)
EM male 0
CM (n = 50)
CM female 19.51
CM male 12.5
Camboim Rockett
2012 [60]
Cross-sectional
Predetermined list
of 22 dietary factors
Migraine (n =
123)
Mean 43.2 ±
13.9
Migraine after
caffeine
consumption
MWA (n = 84)
MA (n = 39)
Occasional 10–15
Consistent <10
Caffeine
withdrawal
Occasional 10–15
Consistent 20–30
Neut 2012 [83]
Retrospective
Predetermined list
of TFs
Migraine (n =
102)
Mean 12
Cola drinks 8.8
Range 7–16
MWA (n = 71)
MA (n = 22)
Schürks 2011 [84]
Cross-sectional
Mailed
migraine-specific
questionnaire
Women′s
Health Study
(n = 1675)
No data
Coffee 8.1
Cola drinks 5

Nutrients 2020, 12, 2259 9 of 16
Yadav 2010 [85]
Prospective
cross-sectional
Questionnaire
Migraine
without aura (n
= 182)
Mean 30.7
None
No subjects
reported coffee or
caffeine
withdrawal as a
trigger
Range
14–58
Hauge 2010 [86]
Cross-sectional
Questionnaire
listing 16 trigger
factors
Migraine with
aura (n = 347)
Mean 51
Caffeine
withdrawal
20–30
Andress-Rothrock
2010 [87]
Prospective
cross-sectional
Headache trigger
checklist
Migraine (n =
200)
Mean 41.1
8
Range
16–75
EM (n = 56)
CM (n = 144)
Chakravarty 2009
[88]
Prospective and
retrospective
cross-sectional
Migraine trigger
checklist
Migraine (n =
200)
Range 7–15
Caffeinated
drinks
MWA (n = 197)
Retrospective
study 0
MA (n = 3)
Prospective
study 0
Fukui 2008 [89]
Prospective
cross-sectional
Predetermined list
of TGGs
Migraine (n =
200)
Mean 37.7
14.5 (12.96%
females, 21.05%
males)
Wöber 2006 [90]
Cross-sectional
Two
predetermined TF
checklists (patients′
personal experience
and theoretical
knowledge)
Migraine (n =
71)
Range
18–65
Theoretical
knowledge 25
Difference
between
theoretical
knowledge and
personal
experience of
coffee was
statistically
significant
Personal
experience 10
TTH (n = 49)
Migraine
36.8 ± 11.4
TTH 39.5 ±
12.7
Takeschima 2004
[91]
Door-to-door
survey
Structured
questionnaires
Headache (n =
1628)
No data
None
Odds ratio of
coffee and tea
consumption
significantly
higher in
migraineurs
compared to TTH
sufferers
migraine (n =
342)
MWA (n = 301)
MA (n = 41)
Bank 2000 [92]
Population-based
epidemiological
survey
Self-administered
headache
questionnaire
Migraine (n =
62)
Mean
None
Women 41
Men 43
Van Den Bergh
1987 [93]
Retrospective
Unstructured
recall/free
self-report
Migraine (n =
217)
Mean 40
6.4
Twenty-one studies evaluated the prevalence of caffeine as a migraine trigger. Among them,
four studies failed to find any participant who reported caffeine as a trigger. In other studies,
caffeine was reported to be a migraine trigger in a small percentage of participants (ranging from
2.4% to 30%). Only two studies examined caffeine withdrawal as a trigger factor, both with a
relatively high percentage of patients (ranging from 10% to 30%) [60,86]. However, it is worth noting
that in most of the studies, patients were asked retrospectively to recall their usual headache triggers
using a predetermined list, thus they mostly assessed beliefs about triggers rather than facts. Only
one study used an electronic diary (supposedly one of the best trigger factor study designs) and
found coffee as a trigger in a very small percentage of migraineurs. Unfortunately, we found no
provocative studies evaluating whether caffeine can provoke migraine attacks. It is reported that a
high level of caffeinated beverage intake may induce a migraine attack on that day. Mostofsky et al.,
in a prospective cohort study, found that although consuming one or two caffeinated beverages was
not associated with the odds of having a migraine on that day, ≥3 beverages was connected to higher
odds of having a headache, even after accounting for potential confounding by other triggers.
Moreover, a nonlinear association between caffeine intake and the odds of migraine occurrence on
that day was found [75]. Taheri et al. examined the effects of dietary exclusion on the course of
primary headache including migraine in a group of children. Interestingly, caffeine was reported as
the most common trigger in this group (28%). After excluding one to three of the identified food
triggers, 87% of patients achieved complete resolution of their headaches, meaning that the
cumulative effect of food rather than a single ingestion influences headaches [78]. In the

Nutrients 2020, 12, 2259 10 of 16
Head-HUNT study, chronic headaches were more prevalent among individuals with low caffeine
intake compared to those with moderate or high intake. Besides, a significant association was found
between high caffeine consumption and the prevalence of infrequent headache (OR = 1.16, 95% CI
1.09–1.23). The authors concluded that high caffeine intake may change chronic headache into
episodic headache due to the analgesic properties of caffeine. Another explanation is that chronic
headache sufferers tend to avoid caffeine so as to not aggravate their headaches [94]. Couturier et al.
revealed that weekend headaches are linked to caffeine withdrawal. They examined 151 patients
with migraine or tension-type headache (TTH) and found that 21.9% of them had weekend
headaches. Weekend headache sufferers consumed significantly more caffeine daily (mean 734
mg/day) and slept longer on weekends compared with those without weekend headaches.
Prolonged weekend sleep delayed the usual cup of coffee, thus produced headache [68]. Camboim
Rockett et al., in a very interesting study, found that coffee withdrawal was more frequently
reported as a migraine trigger than coffee intake. Besides, participants reported that coffee intake
produced migraine attack occasionally, but coffee withdrawal did so frequently. Moreover, coffee
withdrawal was a more prevalent trigger in migraines with aura, and coffee intake was a common
trigger in migraines without aura [60].
3.2. Caffeine as Acute Migraine Treatment
Only one prospective study evaluated separate doses of caffeine in the treatment of acute
migraine attack. Baratloo et al. compared the effectiveness of either 60 mg intravenous caffeine or 2 g
intravenous magnesium sulfate in migraine attacks. Although both treatment options diminished
pain scores significantly, after one hour magnesium was more effective than caffeine [95]. A number
of studies examined the usefulness of caffeine in combination with other analgesics. In a
double-blind randomized placebo-controlled study, a combination of acetaminophen, acetylsalicylic
acid, and caffeine (130 mg) was compared with ibuprofen and placebo for treatment of acute
migraine in patients with severe baseline migraine pain. The combination of drugs relieved the pain
and associated symptoms of severe migraine significantly better and faster than ibuprofen (p ≤ 0.05)
[96]. Another randomized double-blind study compared the efficacy and tolerability of the
combination of paracetamol and caffeine (130 mg) with sumatriptan (50 mg) for migraine attacks.
Surprisingly, both treatments were equally effective and safe with respect to the baseline, with no
differences between the two [97]. In a different double-blind randomized trial, patients treated two
migraine attacks, one with almotriptan 12.5 mg and one with ergotamine plus caffeine (200 mg).
Almotriptan was associated with significantly greater efficacy in treating migraine compared to the
combined drug, and moreover was well tolerated and associated with greater treatment satisfaction
[98]. The effectiveness of a combination analgesic containing acetaminophen, aspirin, and caffeine
(65 mg) was compared with ibuprofen and placebo for migraine attacks. Although both active
treatments were significantly better than placebo in relieving the pain and associated symptoms of
migraine, the combination product provided superior efficacy and speed of onset compared with
ibuprofen [99]. Another study compared the combination of acetaminophen, aspirin, and caffeine
(130 mg) with sumatriptan (50 mg) for treatment of migraine attacks. The combination product was
significantly more effective (p > 0.05) than sumatriptan in the early treatment of migraine [100]. A
randomized double-blind study evaluated the efficacy of 100 mg diclofenac sodium softgel with or
without 100 mg caffeine versus placebo during migraine attacks. Headache relief at 60 min was
reported by 14% of the placebo group versus 27% of the diclofenac group and 41% of the diclofenac
plus caffeine group. Diclofenac softgel plus caffeine produced statistically significant benefits when
compared to placebo at 60 min, while diclofenac softgel alone did not differ significantly from
placebo. Nonsignificant trends support the analgesic adjuvant benefit of caffeine when added to
diclofenac softgels [101].

Nutrients 2020, 12, 2259 11 of 16
3.3. Recommendations for Migraine Patients Regarding Caffeine Use
1. Individuals with migraines must be aware of the amount of caffeine they consume daily. They
should carefully identify all caffeine products consumed daily, including coffee, tea, soft drinks,
energy drinks, and medications.
2. Migraine sufferers who are regular caffeine consumers and wish to continue drinking
caffeinated beverages, should keep their daily caffeine intake as consistent as possible. They
should also choose coffee as a preferable caffeine source because of the additional health
benefit. Those who wish to cease caffeine consumption should gradually taper their intake over
several weeks.
3. Daily intake of caffeine should be limited to less than 200 mg/day (about two servings of
caffeinated beverage).
4. Patients should continue to consume caffeine regularly every day, preferably at a consistent
time, and should not discontinue it during the weekend. They should avoid sleeping longer on
weekends to prevent caffeine withdrawal headache.
5. Caffeine-containing analgesics are safe and effective in treating migraine attacks, but their
consumption should be limited to two days during the week to avoid medication overuse
headache.
4. Conclusions
Although caffeine has been connected to migraine for many years, its effect on headache is
ambiguous. Caffeine or coffee consumption as well as caffeine withdrawal were found to be
migraine trigger factors in a small proportion of migraine patients. However, it may be challenging
to distinguish between migraine triggers and premonitory symptoms, as drinking coffee or an
energy drink before an attack may be due to yawning, diminished energy levels, and sleepiness that
may herald a headache. Besides, no provocative studies have been conducted to confirm that
caffeine can trigger migraines. On the other hand, caffeine alone or as a drug compound was found
to be safe and effective in treating acute migraines. Caffeine may influence migraines through many
possible mechanisms, mostly by adenosine receptor antagonism with further vasoconstriction and
reduced CBF. Although there is a link between caffeine and migraines, a larger prospective study
based on electronic diaries should be performed to assess the connection. Based on our review of the
current literature, there is insufficient evidence to show that a single dose of caffeine is a migraine
trigger; however, it should be emphasized that chronic caffeine overuse may lead to migraine
chronification and sudden caffeine cessation may trigger migraine attacks. Migraine sufferers
should be aware of the amount of caffeine they consume so that they do not exceed 200 mg daily. If
they wish to continue drinking caffeinated beverages, they should keep their daily intake as
consistent as possible to avoid withdrawal headache.
Author Contributions: M.N. contributed to data analysis, interpretation of the findings, and drafting of the
article. M.N. and M.W. participated in data collection. M.W. and W.K. participated in the critical revision and
final approval. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
References
1. Steiner, T.J.; Stovner, L.J.; Birbeck, G.L. Migraine: The seventh disabler. Headache 2013, 53, 227–229.
2. Collaborators, G.H. Global, regional, and national burden of migraine and tension-type headache,
1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2018, 17,
954–976.
3. Headache Classification Committee of the International Headache Society (IHS). The International
Classification of Headache Disorders 3rd edition. Cephalalgia 2018, 38, 1–211.
4. Alstadhaug, K.B.; Andreou, A.P. Caffeine and Primary (Migraine) Headaches-Friend or Foe? Front.
Neurol. 2019, 10, 1275.

Nutrients 2020, 12, 2259 12 of 16
5. Hindiyeh, N.A.; Zhang, N.; Farrar, M.; Banerjee, P.; Lombard, L.; Aurora, S.K. The Role of Diet and
Nutrition in Migraine Triggers and Treatment: A Systematic Literature Review. Headache 2020,
doi:10.1111/head.13836.
6. Lipton, R.B.; Diener, H.C.; Robbins, M.S.; Garas, S.Y.; Patel, K. Caffeine in the management of patients
with headache. J. Headache Pain 2017, 18, 107.
7. Spencer, B. Caffeine withdrawal: A model for migraine? Headache 2002, 42, 561–562.
8. Ward, N.; Whitney, C.; Avery, D.; Dunner, D. The analgesic effects of caffeine in headache. Pain 1991, 44,
151–155.
9. Ogawa, N.; Ueki, H. Clinical importance of caffeine dependence and abuse. Psychiatry Clin. Neurosci. 2007,
61, 263–268.
10. Heckman, M.A.; Weil, J.; Gonzalez de Mejia, E. Caffeine (1, 3, 7-trimethylxanthine) in foods: A
comprehensive review on consumption, functionality, safety, and regulatory matters. J. Food Sci. 2010, 75,
R77–R87.
11. Fried, N.T.; Elliott, M.B.; Oshinsky, M.L. The Role of Adenosine Signaling in Headache: A Review. Brain
Sci. 2017, 7, 30.
12. Baratloo, A.; Rouhipour, A.; Forouzanfar, M.M.; Safari, S.; Amiri, M.; Negida, A. The Role of Caffeine in
Pain Management: A Brief Literature Review. Anesth Pain Med. 2016, 6, e33193.
13. Haskell-Ramsay, C.F.; Jackson, P.A.; Forster, J.S.; Dodd, F.L.; Bowerbank, S.L.; Kennedy, D.O. The Acute
Effects of Caffeinated Black Coffee on Cognition and Mood in Healthy Young and Older Adults.
Nutrients 2018, 10, 1386.
14. Nawrot, P.; Jordan, S.; Eastwood, J.; Rotstein, J.; Hugenholtz, A.; Feeley, M. Effects of caffeine on human
health. Food Addit. Contam. 2003, 20, 1–30.
15. Miners, J.O.; Birkett, D.J. The use of caffeine as a metabolic probe for human drug metabolizing enzymes.
Gen. Pharmacol. 1996, 27, 245–249.
16. Grosso, G.; Godos, J.; Galvano, F.; Giovannucci, E.L. Coffee, Caffeine, and Health Outcomes: An
Umbrella Review. Annu. Rev. Nutr. 2017, 37, 131–156.
17. Nehlig, A. Effects of coffee/caffeine on brain health and disease: What should I tell my patients? Pract.
Neurol. 2016, 16, 89–95.
18. Cornelis, M.C. The Impact of Caffeine and Coffee on Human Health. Nutrients 2019, 11, 416.
19. Bruce, C.; Yates, D.H.; Thomas, P.S. Caffeine decreases exhaled nitric oxide. Thorax 2002, 57, 361–363.
20. Umemura, T.; Ueda, K.; Nishioka, K.; Hidaka, T.; Takemoto, H.; Nakamura, S.; Jitsuiki, D.; Soga, J.; Goto,
C.; Chayama, K.; et al. Effects of acute administration of caffeine on vascular function. Am. J. Cardiol. 2006,
98, 1538–1541.
21. Higashi, Y. Coffee and Endothelial Function: A Coffee Paradox? Nutrients 2019, 11, 2104.
22. Joris, P.J.; Mensink, R.P.; Adam, T.C.; Liu, T.T. Cerebral Blood Flow Measurements in Adults: A Review
on the Effects of Dietary Factors and Exercise. Nutrients 2018, 10, 530.
23. Gererd, D. Coffee and Health; John Libbey Eurotext: Esher, UK, 1994.
24. Vidyasagar, R.; Greyling, A.; Draijer, R.; Corfield, D.R.; Parkes, L.M. The effect of black tea and caffeine
on regional cerebral blood flow measured with arterial spin labeling. J. Cereb. Blood Flow Metab. 2013, 33,
963–968.
25. Haanes, K.A.; Labastida-Ramírez, A.; Chan, K.Y.; de Vries, R.; Shook, B.; Jackson, P.; Zhang, J.; Flores,
C.M.; Danser, A.H.J.; Villalón, C.M.; et al. Characterization of the trigeminovascular actions of several
adenosine A. J. Headache Pain 2018, 19, 41.
26. Yang, H.S.; Liang, Z.; Yao, J.F.; Shen, X.; Frederick, B.D.; Tong, Y. Vascular effects of caffeine found in
BOLD fMRI. J. Neurosci. Res. 2019, 97, 456–466.
27. Xu, F.; Liu, P.; Pekar, J.J.; Lu, H. Does acute caffeine ingestion alter brain metabolism in young adults?
Neuroimage 2015, 110, 39–47.
28. Blaha, M.; Benes, V.; Douville, C.M.; Newell, D.W. The effect of caffeine on dilated cerebral circulation
and on diagnostic CO2 reactivity testing. J. Clin. Neurosci. 2007, 14, 464–467.
29. Lunt, M.J.; Ragab, S.; Birch, A.A.; Schley, D.; Jenkinson, D.F. Comparison of caffeine-induced changes in
cerebral blood flow and middle cerebral artery blood velocity shows that caffeine reduces middle
cerebral artery diameter. Physiol. Meas. 2004, 25, 467–474.

Nutrients 2020, 12, 2259 13 of 16
30. Addicott, M.A.; Yang, L.L.; Peiffer, A.M.; Burnett, L.R.; Burdette, J.H.; Chen, M.Y.; Hayasaka, S.; Kraft,
R.A.; Maldjian, J.A.; Laurienti, P.J. The effect of daily caffeine use on cerebral blood flow: How much
caffeine can we tolerate? Hum. Brain Mapp. 2009, 30, 3102–3114.
31. Couturier, E.G.; Laman, D.M.; van Duijn, M.A.; van Duijn, H. Influence of caffeine and caffeine
withdrawal on headache and cerebral blood flow velocities. Cephalalgia 1997, 17, 188–190.
32. Sigmon, S.C.; Herning, R.I.; Better, W.; Cadet, J.L.; Griffiths, R.R. Caffeine withdrawal, acute effects,
tolerance, and absence of net beneficial effects of chronic administration: Cerebral blood flow velocity,
quantitative EEG, and subjective effects. Psychopharmacology (Berl.) 2009, 204, 573–585.
33. Marchand, S.; Li, J.; Charest, J. Effects of caffeine on analgesia from transcutaneous electrical nerve
stimulation. N. Engl. J. Med. 1995, 333, 325–326.
34. Derry, C.J.; Derry, S.; Moore, R.A. Caffeine as an analgesic adjuvant for acute pain in adults. Cochrane
Database Syst. Rev. 2014, doi:10.1002/14651858.CD009281.pub3.
35. Laska, E.M.; Sunshine, A.; Mueller, F.; Elvers, W.B.; Siegel, C.; Rubin, A. Caffeine as an analgesic
adjuvant. JAMA 1984, 251, 1711–1718.
36. Zaeem, Z.; Zhou, L.; Dilli, E. Headaches: A Review of the Role of Dietary Factors. Curr. Neurol. Neurosci.
Rep. 2016, 16, 101.
37. Liang, J.F.; Wang, S.J. Hypnic headache: A review of clinical features, therapeutic options and outcomes.
Cephalalgia 2014, 34, 795–805.
38. Basurto Ona, X.; Osorio, D.; Bonfill Cosp, X. Drug therapy for treating post -dural puncture headache.
Cochrane Database Syst. Rev. 2015, doi:10.1002/14651858.CD007887.pub3.
39. Han, M.E.; Kim, H.J.; Lee, Y.S.; Kim, D.H.; Choi, J.T.; Pan, C.S.; Yoon, S.; Baek, S.Y.; Kim, B.S.; Kim, J.B.; et
al. Regulation of cerebrospinal fluid production by caffeine consumption. BMC Neurosci. 2009, 10, 110.
40. Kalladka, D.; Siddiqui, A.; Tyagi, A.; Newman, E. Reversible cerebral vasoconstriction syndrome
secondary to caffeine withdrawal. Scott. Med. J. 2018, 63, 22–24.
41. Chattha, N.; Webb, T.; Hargroves, D.; Balogun, I.; Bertoni, M. Reversible cerebral vasoconstriction
syndrome after sudden caffeine withdrawal. Br. J. Hosp. Med. (Lond.) 2019, 80, 730–731.
42. Manzoni, G.C. Cluster headache and lifestyle: Remarks on a population of 374 male patients. Cephalalgia
1999, 19, 88–94.
43. Scher, A.I.; Stewart, W.F.; Lipton, R.B. Caffeine as a risk factor for chronic daily headache: A
population-based study. Neurology 2004, 63, 2022–2027.
44. Kluonaitis, K.; Petrauskiene, E.; Ryliskiene, K. Clinical characteristics and overuse patterns of medication
overuse headache: Retrospective case-series study. Clin. Neurol. Neurosurg. 2017, 163, 124–127.
45. Dong, Z.; Chen, X.; Steiner, T.J.; Hou, L.; Di, H.; He, M.; Dai, W.; Pan, M.; Zhang, M.; Liu, R.; et al.
Medication-overuse headache in China: Clinical profile, and an evaluation of the ICHD-3 beta diagnostic
criteria. Cephalalgia 2015, 35, 644–651.
46. Diamond, S.; Balm, T.K.; Freitag, F.G. Ibuprofen plus caffeine in the treatment of tension-type headache.
Clin. Pharmacol. Ther. 2000, 68, 312–319.
47. Jacobs, B.; Dussor, G. Neurovascular contributions to migraine: Moving beyond vasodilation.
Neuroscience 2016, 338, 130–144.
48. Guieu, R.; Devaux, C.; Henry, H.; Bechis, G.; Pouget, J.; Mallet, D.; Sampieri, F.; Juin, M.; Gola, R.; Rochat,
H. Adenosine and migraine. Can. J. Neurol. Sci. 1998, 25, 55–58.
49. Aurora, S.K.; Kori, S.H.; Barrodale, P.; McDonald, S.A.; Haseley, D. Gastric stasis in migraine: More than
just a paroxysmal abnormality during a migraine attack. Headache 2006, 46, 57–63.
50. Silberstein, S. Gastrointestinal manifestations of migraine: Meeting the treatment challenges. Headache
2013, 53, 1–3.
51. Messlinger, K.; Lennerz, J.K.; Eberhardt, M.; Fischer, M.J. CGRP and NO in the trigeminal system:
Mechanisms and role in headache generation. Headache 2012, 52, 1411–1427.
52. González, S.; Salazar, N.; Ruiz-Saavedra, S.; Gómez-Martín, M.; de Los Reyes-Gavilán, C.G.; Gueimonde,
M. Long-Term Coffee Consumption is Associated with Fecal Microbial Composition in Humans.
Nutrients 2020, 12, 1287.
53. Arzani, M.; Jahromi, S.R.; Ghorbani, Z.; Vahabizad, F.; Martelletti, P.; Ghaemi, A.; Sacco, S.; Togha, M.;
On behalf of the School of Advanced Studies of the European Headache Federation (EHF-SAS). Gut-brain
Axis and migraine headache: A comprehensive review. J. Headache Pain 2020, 21, 15.

Nutrients 2020, 12, 2259 14 of 16
54. Martami, F.; Togha, M.; Seifishahpar, M.; Ghorbani, Z.; Ansari, H.; Karimi, T.; Jahromi, S.R. The effects of
a multispecies probiotic supplement on inflammatory markers and episodic and chronic migraine
characteristics: A randomized double-blind controlled trial. Cephalalgia 2019, 39, 841–853.
55. Lipton, R.B.; Pavlovic, J.M.; Haut, S.R.; Grosberg, B.M.; Buse, D.C. Methodological issues in studying
trigger factors and premonitory features of migraine. Headache 2014, 54, 1661–1669.
56. Peroutka, S.J. What turns on a migraine? A systematic review of migraine precipitating factors. Curr. Pain
Headache Rep. 2014, 18, 454.
57. Mollaoğlu, M. Trigger factors in migraine patients. J. Health Psychol. 2013, 18, 984–994.
58. Hoffmann, J.; Recober, A. Migraine and triggers: Post hoc ergo propter hoc? Curr. Pain Headache Rep. 2013,
17, 370.
59. Wöber, C.; Wöber-Bingöl, C. Triggers of migraine and tension-type headache. Handb. Clin. Neurol. 2010,
97, 161–172.
60. Rockett, F.C.; Castro, K.; de Oliveira, V.R.; da Silveira, P.A.; Chaves, M.L.F.; Perry, I.D.S. Perceived
migraine triggers: Do dietary factors play a role? Nutr. Hosp. 2012, 27, 483–489.
61. Aguggia, M.; Saracco, M.G. Pathophysiology of migraine chronification. Neurol. Sci. 2010, 31, S15–S17.
62. Bigal, M.E.; Lipton, R.B. Modifiable risk factors for migraine progression. Headache 2006, 46, 1334–1343.
63. Guendler, V.Z.; Mercante, J.P.; Ribeiro, R.T.; Zukerman, E.; Peres, M.F. Factors associated with acute
medication overuse in chronic migraine patients. Einstein (Sao Paulo) 2012, 10, 312–317.
64. Bergman, E.A.; Massey, L.K.; Wise, K.J.; Sherrard, D.J. Effects of dietary caffeine on renal handling of
minerals in adult women. Life Sci. 1990, 47, 557–564.
65. Kirkland, A.E.; Sarlo, G.L.; Holton, K.F. The Role of Magnesium in Neurological Disorders. Nutrients
2018, 10, 730.
66. Wöber, C.; Brannath, W.; Schmidt, K.; Kapitan, M.; Rudel, E.; Wessely, P.; Wöber-Bingöl, C.; Group, P.S.
Prospective analysis of factors related to migraine attacks: The PAMINA study. Cephalalgia 2007, 27,
304–314.
67. Seal, A.D.; Bardis, C.N.; Gavrieli, A.; Grigorakis, P.; Adams, J.D.; Arnaoutis, G.; Yannakoulia, M.;
Kavouras, S.A. Coffee with High but Not Low Caffeine Content Augments Fluid and Electrolyte
Excretion at Rest. Front. Nutr. 2017, 4, 40.
68. Couturier, E.G.; Hering, R.; Steiner, T.J. Weekend attacks in migraine patients: Caused by caffeine
withdrawal? Cephalalgia 1992, 12, 99–100.
69. Schulte, L.H.; Jürgens, T.P.; May, A. Photo-, osmo- and phonophobia in the premonitory phase of
migraine: Mistaking symptoms for triggers? J. Headache Pain 2015, 16, 14.
70. Yalcin, N.; Chen, S.P.; Yu, E.S.; Liu, T.T.; Yen, J.C.; Atalay, Y.B.; Qin, T.; Celik, F.; van den Maagdenberg,
A.M.; Moskowitz, M.A.; et al. Caffeine does not affect susceptibility to cortical spreading depolarization
in mice. J. Cereb. Blood Flow Metab. 2019, 39, 740–750.
71. Goadsby, P.J.; Silberstein, S.D. Migraine triggers: Harnessing the messages of clinical practice. Neurology
2013, 80, 424–425.
72. Martin, P.R. Managing headache triggers: Think ‘coping’ not ‘avoidance’. Cephalalgia 2010, 30, 634–637.
73. Mikulec, A.A.; Faraji, F.; Kinsella, L.J. Evaluation of the efficacy of caffeine cessation, nortriptyline, and
topiramate therapy in vestibular migraine and complex dizziness of unknown etiology. Am. J.
Otolaryngol. 2012, 33, 121–127.
74. Lee, M.J.; Choi, H.A.; Choi, H.; Chung, C.S. Caffeine discontinuation improves acute migraine treatment:
A prospective clinic-based study. J. Headache Pain 2016, 17, 71.
75. Mostofsky, E.; Mittleman, M.A.; Buettner, C.; Li, W.; Bertisch, S.M. Prospective Cohort Study of
Caffeinated Beverage Intake as a Potential Trigger of Headaches among Migraineurs. Am. J. Med. 2019,
132, 984–991.
76. Beh, S.C.; Masrour, S.; Smith, S.V.; Friedman, D.I. The Spectrum of Vestibular Migraine: Clinical Features,
Triggers, and Examination Findings. Headache 2019, 59, 727–740.
77. Tai, M.S.; Yap, J.F.; Goh, C.B. Dietary trigger factors of migraine and tension-type headache in a South
East Asian country. J. Pain Res. 2018, 11, 1255–1261.
78. Taheri, S. Effect of exclusion of frequently consumed dietary triggers in a cohort of children with chronic
primary headache. Nutr. Health 2017, 23, 47–50.
79. Park, J.W.; Chu, M.K.; Kim, J.M.; Park, S.G.; Cho, S.J. Analysis of Trigger Factors in Episodic Migraineurs
Using a Smartphone Headache Diary Applications. PLoS ONE 2016, 11, e0149577.

Nutrients 2020, 12, 2259 15 of 16
80. Peris, F.; Donoghue, S.; Torres, F.; Mian, A.; Wöber, C. Towards improved migraine management:
Determining potential trigger factors in individual patients. Cephalalgia 2017, 37, 452–463.
81. Rist, P.M.; Buring, J.E.; Kurth, T. Dietary patterns according to headache and migraine status: A
cross-sectional study. Cephalalgia 2015, 35, 767–775.
82. Fraga, M.D.; Pinho, R.S.; Andreoni, S.; Vitalle, M.S.; Fisberg, M.; Peres, M.F.; Vilanova, L.C.; Masruha,
M.R. Trigger factors mainly from the environmental type are reported by adolescents with migraine. Arq.
Neuropsiquiatr. 2013, 71, 290–293.
83. Neut, D.; Fily, A.; Cuvellier, J.C.; Vallée, L. The prevalence of triggers in paediatric migraine: A
questionnaire study in 102 children and adolescents. J. Headache Pain 2012, 13, 61–65.
84. Schürks, M.; Buring, J.E.; Kurth, T. Migraine features, associated symptoms and triggers: A principal
component analysis in the Women’s Health Study. Cephalalgia 2011, 31, 861–869.
85. Yadav, R.K.; Kalita, J.; Misra, U.K. A study of triggers of migraine in India. Pain Med. 2010, 11, 44–47.
86. Hauge, A.W.; Kirchmann, M.; Olesen, J. Trigger factors in migraine with aura. Cephalalgia 2010, 30,
346–353.
87. Andress-Rothrock, D.; King, W.; Rothrock, J. An analysis of migraine triggers in a clinic-based
population. Headache 2010, 50, 1366–1370.
88. Chakravarty, A.; Mukherjee, A.; Roy, D. Trigger factors in childhood migraine: A clinic-based study from
eastern India. J. Headache Pain 2009, 10, 375–380.
89. Fukui, P.T.; Gonçalves, T.R.; Strabelli, C.G.; Lucchino, N.M.; Matos, F.C.; Santos, J.P.; Zukerman, E.;
Zukerman-Guendler, V.; Mercante, J.P.; Masruha, M.R.; et al. Trigger factors in migraine patients. Arq.
Neuropsiquiatr. 2008, 66, 494–499.
90. Wöber, C.; Holzhammer, J.; Zeitlhofer, J.; Wessely, P.; Wöber-Bingöl, C. Trigger factors of migraine and
tension-type headache: Experience and knowledge of the patients. J. Headache Pain 2006, 7, 188–195.
91. Takeshima, T.; Ishizaki, K.; Fukuhara, Y.; Ijiri, T.; Kusumi, M.; Wakutani, Y.; Mori, M.; Kawashima, M.;
Kowa, H.; Adachi, Y.; et al. Population-based door-to-door survey of migraine in Japan: The Daisen
study. Headache 2004, 44, 8–19.
92. Bánk, J.; Márton, S. Hungarian migraine epidemiology. Headache 2000, 40, 164–169.
93. Van den Bergh, V.; Amery, W.K.; Waelkens, J. Trigger factors in migraine: A study conducted by the
Belgian Migraine Society. Headache 1987, 27, 191–196.
94. Hagen, K.; Thoresen, K.; Stovner, L.J.; Zwart, J.A. High dietary caffeine consumption is associated with a
modest increase in headache prevalence: Results from the Head-HUNT Study. J. Headache Pain 2009, 10,
153–159.
95. Baratloo, A.; Mirbaha, S.; Delavar Kasmaei, H.; Payandemehr, P.; Elmaraezy, A.; Negida, A. Intravenous
caffeine citrate vs. magnesium sulfate for reducing pain in patients with acute migraine headache; a
prospective quasi-experimental study. Korean J. Pain 2017, 30, 176–182.
96. Goldstein, J.; Hagen, M.; Gold, M. Results of a multicenter, double-blind, randomized, parallel-group,
placebo-controlled, single-dose study comparing the fixed combination of acetaminophen, acetylsalicylic
acid, and caffeine with ibuprofen for acute treatment of patients with severe migraine. Cephalalgia 2014,
34, 1070–1078.
97. Pini, L.A.; Guerzoni, S.; Cainazzo, M.; Ciccarese, M.; Prudenzano, M.P.; Livrea, P. Comparison of
tolerability and efficacy of a combination of paracetamol + caffeine and sumatriptan in the treatment of
migraine attack: A randomized, double-blind, double-dummy, cross-over study. J. Headache Pain 2012, 13,
669–675.
98. Láinez, M.J.; Galván, J.; Heras, J.; Vila, C. Crossover, double-blind clinical trial comparing almotriptan
and ergotamine plus caffeine for acute migraine therapy. Eur. J. Neurol. 2007, 14, 269–275.
99. Goldstein, J.; Silberstein, S.D.; Saper, J.R.; Ryan, R.E.; Lipton, R.B. Acetaminophen, aspirin, and caffeine in
combination versus ibuprofen for acute migraine: Results from a multicenter, double-blind, randomized,
parallel-group, single-dose, placebo-controlled study. Headache 2006, 46, 444–453.

Nutrients 2020, 12, 2259 16 of 16
100. Goldstein, J.; Silberstein, S.D.; Saper, J.R.; Elkind, A.H.; Smith, T.R.; Gallagher, R.M.; Battikha, J.P.;
Hoffman, H.; Baggish, J. Acetaminophen, aspirin, and caffeine versus sumatriptan succinate in the early
treatment of migraine: Results from the ASSET trial. Headache 2005, 45, 973–982.
101. Peroutka, S.J.; Lyon, J.A.; Swarbrick, J.; Lipton, R.B.; Kolodner, K.; Goldstein, J. Efficacy of diclofenac
sodium softgel 100 mg with or without caffeine 100 mg in migraine without aura: A randomized,
double-blind, crossover study. Headache 2004, 44, 136–141.
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).