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


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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.
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Nutrients 2020, 12, 2259; doi:10.3390/nu12082259
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;
3 Department of Sensory Organs Examination, Faculty of Health Sciences, Collegium Medicum in Bydgoszcz,
Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland;
* Correspondence:; 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 [48]. 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 30120 min) and freely crosses the bloodbrain 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 (300400 mg, around 45 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 Parkinsons 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 Parkinsons or Alzheimers 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 (150200 mg) can improve mood states and
decreases the risk of depression and suicide [17].
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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, caffeines 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. Caffeines 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 1015 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 adenosines 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
gutbrain 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
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: CBFCerebral blood flow, CVRCerebrovascular resistance,
CSFCerebrospinal fluid, NONitric oxide, MgMagnesium.
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
Trigger Factors)
Age (Years)
Reported as a
Trigger Factor
Beh 2019 [76]
Retrospective chart
No data
Tai 2018 [77]
dietary checklist
37.1 ± 14.3
Migraine 25.4
associated with
compared to TTH
TTH 15.1
TTH 46.5 ±
Taheri 2017 [78]
observational case
Food diary
87% of patients
achieved complete
resolution of
headaches by
exclusion of 13
Mean 10.5
Park 2016 [79]
headache diary
Mean 37.7 ±
Peris 2016 [80]
Detailed 90-day
paper diary
database from
PAMINA migraine
No data
Rist 2014 [81]
study among
participants in the
Women’s Health
food frequency
Mean 53.6
Not applicable
Patients with
headache more
likely to have low
intake of coffee;
women who
migraine were less
likely to have low
intake of coffee
compared to those
with non-migraine
Mollaoglu 2013
Interview TF
Mean 36.32
Fraga 2013 [82]
Predetermined list
of trigger factors
Total 14
EM female 17.85
EM male 0
CM female 19.51
CM male 12.5
Camboim Rockett
2012 [60]
Predetermined list
of 22 dietary factors
Mean 43.2 ±
Migraine after
Occasional 1015
Consistent <10
Occasional 1015
Consistent 2030
Neut 2012 [83]
Predetermined list
of TFs
Mean 12
Cola drinks 8.8
Range 716
Schürks 2011 [84]
No data
Coffee 8.1
Cola drinks 5
Nutrients 2020, 12, 2259 9 of 16
Yadav 2010 [85]
Mean 30.7
No subjects
reported coffee or
withdrawal as a
Hauge 2010 [86]
listing 16 trigger
Mean 51
2010 [87]
Headache trigger
Mean 41.1
Chakravarty 2009
Prospective and
Migraine trigger
Range 715
study 0
study 0
Fukui 2008 [89]
Predetermined list
of TGGs
Mean 37.7
14.5 (12.96%
females, 21.05%
Wöber 2006 [90]
predetermined TF
checklists (patients′
personal experience
and theoretical
knowledge 25
knowledge and
experience of
coffee was
experience 10
36.8 ± 11.4
TTH 39.5 ±
Takeschima 2004
No data
Odds ratio of
coffee and tea
higher in
compared to TTH
Bank 2000 [92]
Women 41
Men 43
Van Den Bergh
1987 [93]
Mean 40
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
1.091.23). 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
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.
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... Both types of pain are associated with other medical comorbidities, such as sleep disorders, cardiovascular diseases and psychiatric diseases, and affect a variety of areas of the patient's life, from the welfare of individuals and their families, to the academic, occupational and social spheres. [9][10] Pain crises can last from 4 to 72 hours when untreated and, since it is a very complex disease, can be triggered by several causes, the most common of which are stress, fasting, sleep disorders, auditory stimuli and scents, as well as dietary constituents, such as alcohol, dairy products, monosodium glutamate, aspartame, nitrites, chocolate, among others. [11][12] The main drugs used to treat pain are over-thecounter medications, chosen according to the intensity of the pain, 13 such as non-steroidal anti-inflammatory drugs and combined analgesics containing aspirin, paracetamol and caffeine, which are considered first-line treatments for mild to severe migraines, 14 as well as triptans, which are indicated for the first-line treatment of moderate to severe cases, since evidence shows that the combination of analgesics increases the effectiveness of the treatment. ...
... In addition to coffee, caffeine is found in teas, chocolates, guarana, cocoa, among other foods. 9 Because their structure is similar to that of adenosine, caffeine molecules act as competitive inhibitors, canceling the action of adenosine, which is responsible for inhibiting excitatory neurotransmitters, and generating a drop in cortical excitability. 21 In addition, adenosine is one of the neuromodulators that favor the pathophysiology of acute pain. ...
... 21 In addition, adenosine is one of the neuromodulators that favor the pathophysiology of acute pain. 9 Another mechanism of action of caffeine in the body relates to gastric performance. During an acute pain crisis, gastric motility falls and, consequently, drug absorption is delayed. ...
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Migraine is a complex illness characterized by moderate to severe headache attacks, affecting more than a billion people worldwide. Its treatment is mainly done by over-the-counter medications, and most of them are drugs combined with caffeine. Objective – To analyze whether analgesics combined with caffeine are more effective for the treatment of a migraine attack than analgesics not combined with caffeine. Methods – A systematic review was carried out based on scientific articles published in databases such as SCIELO, PubMed and Science Direct. We analyzed 15 original articles with clinical trials and controlled trials that evaluated the efficacy of analgesics combined with caffeine and published between 2010 and 2020. Results – Among the 15 studies analyzed, a total of 5,030 patients were evaluated. Of these studies,10 concluded that analgesics associated with caffeine are more effective for the treatment of a migraine attack, 4 studies concluded that the two types of analgesics are equally effective and 1 study concluded that the non-combined analgesic is more effective for the treatment. Conclusion – analgesics combined with caffeine are more effective for the treatment of a migraine attack, as they promote pain relief in less time, managing to completely stop the pain. Caffeine is believed to act by inhibiting cyclooxygenase in some locations and by blocking central and peripheral adenosine receptors.
... In addition, the discontinuation of caffeine consumption may cause headaches after approximately 24 h among chronic caffeine takers [7]. The American Psychiatric Association has listed caffeine withdrawal symptoms in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. ...
... The neural activity of some brain regions decreases during some types of movements and increases during rest [7,9]. In addition to the increase in blood oxygenation level-dependent (BOLD) signal, resting-state signals are consistent low-frequency fluctuations in the range of 0.01-0.08 ...
... In addition to the increase in blood oxygenation level-dependent (BOLD) signal, resting-state signals are consistent low-frequency fluctuations in the range of 0.01-0.08 Hz [7,9]. Approximately 60%-80% of energy is consumed by the whole brain at rest [10]. ...
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Caffeine is a psychoactive substance that not only improves wakefulness, but also slows the cognitive decline caused by aging. However, at present, there are no reports about the effects of caffeine withdrawal, including headaches and changes in brain functional networks (nerve activity). Headache may occur approximately 24 h after discontinuing caffeine intake in chronic caffeine drinkers. The current study aimed to examine the brain functional activity via resting-state functional magnetic resonance imaging in chronically caffeinated and decaffeinated groups to investigate changes in brain activity caused by caffeine. C57BL/6J mice were included in the analysis, and they underwent 9.4-T ultrahigh-field magnetic resonance imaging. The mice were classified into the control, chronic caffeinated, and caffeine withdrawal grsoups. Mice were divided into three groups: 1) not exposed to caffeine (control); 2) treated with caffeine at a concentration of 0.3 mg/mL for 4 weeks (chronic caffeinated); and 3) treated as before with caffeine and withdrawn from caffeine for 24 h. After the three groups were examined, functional connectivity matrices were calculated using brain imaging analysis tools, and independent component analysis was performed. The results showed that caffeine administration activated neural activity areas in the stress response system. Furthermore, 24h after caffeine withdrawal, the results showed an increase in pain-related neural activity. In addition, caffeine administration was shown to activate the dentate gyrus, one of the hippocampal regions, and to decrease the neural activity in the olfactory bulb and anterior cingulate cortex. In the current research, the neural activity of specific brain regions changed after chronic caffeine administration and withdrawal.
... In a retrospective chart review, caffeine cessation led to a reduction in self-reported symptoms of vestibular migraine in 14% of the patients. 53 In another prospective study on 28 patients, lifestyle measures alone led to a reduction in participants' perceived dizziness handicap and headache disability. Of note, restful sleep was particularly helpful in reducing symptoms of both dizziness and headache, with 39% of participants reporting a significant reduction in dizziness handicap and 18% of patients reporting improvement in headache disability. ...
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Vestibular migraine is a leading cause of vertigo in pregnancy and, although not a distinct migraine subtype, is an episodic syndrome associated with migraine. Vestibular migraine is associated with diverse symptoms such as vertigo, aura, allodynia, osmophobia, nausea, vomiting and tinnitus, many of which may be exacerbated by, masked or even dismissed in pregnancy. Vestibular migraine is likely an underdiagnosed and undertreated condition in pregnancy. The aetiology of vestibular migraine remains incompletely understood, although various theories have been proposed, including genetic predisposition, neurochemical dysregulation and pro-inflammatory mechanisms, all of which are derived from the pathophysiology of classical migraine. Physiologic changes to the endocrine, haematologic and vascular systems in pregnancy may affect pathophysiological processes in vestibular migraine, and can alter the course of symptoms experienced in pregnancy. These changes also predispose to secondary headache disorders, which may have similar presentations. There has been considerable progress in therapeutic advances in vestibular migraine prophylaxis and treatment outside of pregnancy. There is currently no significant evidence base for acute treatment or prophylaxis for pregnant patients, with treatment recommendations extrapolated from studies on classical migraine, and offered on a benefit versus risk basis. Challenges commonly encountered include difficulty establishing a diagnosis, in addition to recognising and treating neuropsychiatric and gestational co-morbidities. Anxiety, depression, hypertensive disorders and cardiovascular disease are closely associated with migraine, and important contributors to morbidity and mortality during pregnancy. Identifying and treating vestibular migraine during pregnancy offers a unique opportunity to impact future patient health through screening and early treatment of associated co-morbidities. There have been innovations in classical migraine therapy that may confer benefit in vestibular migraine in pregnancy, with emphasis on lifestyle modification, effective prophylaxis, abortive therapies, cognitive behaviour therapy and management of vestibular migraine-related comorbidities.
... Interestingly, in a meta-analysis of studies about the effects of caffeine on Parkinson's disease (PD) caffeine appeared to both lower the rate of PD progression in patients suffering from the disease as well as decrease the risk of developing PD in the healthy population [7]. On the other hand, several studies have noted that an adjustment may be needed for an individual's caffeine dosage in relation to their age, sex and health conditions to maximize the positive and limit negative effects [8] [9]. ...
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Xanthines such as caffeine and theobromine are among the most consumed psychoactive stimulants in the world, either as natural components of coffee, tea and chocolate, or as food additives. The present study assessed if xanthines affect liver sinusoidal endothelial cells (LSEC). Cultured primary rat LSEC were challenged with xanthines at concentrations typically obtained from normal consumption of xanthine-containing beverages, food or medicines; and at higher concentrations below the in vitro toxic limit. The fenestrated morphology of LSEC were examined with scanning electron and structured illumination microscopy. All xanthine challenges had no toxic effects on LSEC ultrastructure as judged by LSEC fenestration morphology, or function as determined by endocytosis studies. All xanthines in high concentrations (150 μg/mL) increased fenestration frequency but at physiologically relevant concentrations, only theobromine (8 μg/mL) showed an effect. LSEC porosity was influenced only by high caffeine doses which also shifted the fenestration distribution towards smaller pores. Moreover, a dose-dependent increase in fenestration number was observed after caffeine treatment. If these compounds induce similar changes in vivo, age-related reduction of LSEC porosity can be reversed by oral treatment with theobromine or with other xanthines using targeted delivery.
... Kafein bazı çalışmalarda önemli bir migren tetikleyicisi olarak bildirilmiştir (18). Diğer yandan bazı çalışmalarda ise kafein kesilmesi durumunun bir migren tetikleyicisi olduğu ileri sürülmüştür (8,19,20). Bizim çalışma grubumuzda hastaların sadece onda biri kafeini bir tetikleyici olarak ifade etti. Bu durum ülkemizde kafein alım sıklığının ve günlük kafein tüketiminin batı toplumuna kıyasla daha az olması ile açıklanabilir (21). ...
... Frontiers in Pharmacology patients with migraine had higher attack frequencies after caffeine withdrawal, and the migraine attack frequency might gradually decrease when patients keep a stable use of caffeine (<200 mg/day) (Nowaczewska et al., 2020). ...
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Objective: To examine the causal effect of potentially modifiable risk factors contributing to migraine pathogenesis. Methods: We performed Mendelian randomization analyses and acquired data from United Kingdom Biobank, FinnGen Biobank, and the MRC IEU OpenGWAS data infrastructure. An inverse-variance weighted (IVW) model was used to examine the relationship between 51 potentially modifiable risk factors and migraine in 3215 participants with migraine without aura (MwoA), 3541 participants with migraine with aura (MwA), and 176,107 controls. We adopted a Bonferroni-corrected threshold of p = 9.8 × 10–4 (.05 divided by 51 exposures) as a sign of significant effect, and a p < .05 was considered as the sign of a suggestive association. Results: More years of schooling significantly correlated with lower odds of MwoA pathogenesis (OR .57 [95%CI .44 to .75], p < .0001). More vitamin B12 intake (OR .49 [95%CI .24 to .99], p = .046) and lower level of stress [OR 8.17 (95%CI 1.5 to 44.36), p = .015] or anxiety disorder (OR 1.92 × 109 [95%CI 8.76 to 4.23*1017], p = .029) were suggestive to be correlated lower odds of MwoA pathogenesis. More coffee intake (OR .39 [95%CI .22 to .7], p = .001), lower level of eicosapentaenoic acid status (OR 2.54 [95%CI 1.03 to 6.26], p = .043), and more light physical activity (OR .09 [95%CI .01 to .94], p = .046) were suggestive to be associated with lower odds of MwA. Conclusion: The years of schooling, light physical activity, vitamin B12 intake, and coffee intake were the protective factors for migraine; stress, anxiety, and eicosapentaenoic acid status were harmful factors. Interventions could be developed based on modifying these factors for migraine prophylaxis.
... However, each item might or might not trigger one person, and recording the possible stimulating factors helps the patient with migraine find the offenders. For caffeine consumption, attacks occur, especially due to its withdrawal in chronic consumption or its rebound effect in over usage [27,38,52,54,[57][58][59]. The daily consumption of caffeine is recommended to be lower than 200 mg [60]. Although the existing evidence supports the effect of different diets on migraine characteristics, there is no specific diet recommendation for migraine patients [27,52]. ...
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Migraine is a highly prevalent disorder with an enormous burden on societies. Different types of medications are used for controlling both acute attacks and prevention. This article reviews some non-pharmacological recommendations aiming to manage migraine disorder better and prevent headache attacks. Different triggers of migraine headache attacks, including environmental factors, sleep pattern changes, diet, physical activity, stress and anxiety, some medications, and hormonal changes, are discussed. It is advised that they be identified and managed. Patients should learn the skills to cope with the trigger factors that are difficult to avoid. In addition, weight control, management of migraine comorbidities, lifestyle modification, behavioural treatment and biofeedback, patient education, using headache diaries, and improving patients’ knowledge about the disease are recommended to be parts of migraine management. In addition, using neuromodulation techniques, dietary supplements such as riboflavin, coenzyme Q10 and magnesium, and acupuncture can be helpful. Non-pharmacological approaches should be considered in migraine management. Furthermore, the combination of pharmacological and non-pharmacological approaches is more effective than using each separately.
... Tea is an excellent alternative to energy drinks and coffee. Even though tea and coffee have multiple health benefits in common, such their caffeine and antioxidant contents [71,72], excessive coffee drinking (daily intake ≥400 mg for adults (4-5 cups of coffee) and ≥3 mg/kg for children [73]) may contribute to various adverse effects, such as headache [74], insomnia [75][76][77][78][79][80][81][82] and arrhythmia [75,[82][83][84][85] due to caffeinism [76,82,86]. Compared to tea, coffee contains a higher concentration of caffeine, an energy-boosting psychostimulant. ...
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Fermentation is one of the world’s oldest techniques for food preservation, nutrient enhancement, and alcohol manufacturing. During fermentation, carbohydrates such as glucose and starch are converted into other molecules, such as alcohol and acid, anaerobically through enzymatic action while generating energy for the microorganism or cells involved. Black tea is among the most popular fermented beverages; it is made from the dried tea leaves of the evergreen shrub plant known as Camellia sinensis. The adequate consumption of black tea is beneficial to health as it contains high levels of flavanols, also known as catechins, which act as effective antioxidants and are responsible for protecting the body against the development of illnesses, such as inflammation, diabetes, hypertension, cancer, and obesity. The prevalence of obesity is a severe public health concern associated with the incidence of various serious diseases and is now increasing, including in Malaysia. Advances in ‘omic’ research have allowed researchers to identify the pivotal role of the gut microbiota in the development of obesity. This review explores fermented black tea and its correlation with the regulation of the gut microbiota and obesity.
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Disruption of the endothelial barrier function and reduction in cell migration leads to endothelial dysfunction. One of the most abundant human milk oligosaccharides, 6′-sialylactose (6′-SL), is reported to exert various biological functions related to inflammatory responses. In this study, we evaluated the effects of 6′-SL on lipopolysaccharide (LPS)-induced inflammation caused by endothelial barrier damage. Our results showed that LPS at 500 ng/mL strongly not only abolished cell migration but also hyperactivated MAPK and NF-κB pathways. 6′-SL suppressed LPS-induced endothelial inflammation via ERK1/2, p38, and JNK MAPK pathways. 6′-SL supported endothelial junctions by upregulating PECAM-1 expression and mRNA levels of tight junctions, such as ZO-1 and occludin, which were downregulated by LPS stimulation. It significantly inhibited the nuclear translocation of NF-κB, along with the downregulation of inflammatory cytokines, including TNF-α, IL-1β, MCP-1, VCAM-1, and ICAM-1. Furthermore, 6′-SL abolished NF-κB-mediated STAT3 in controlling endothelial migration and hyperpermeability via downregulating STAT3 activation and nuclear translocation. Finally, LPS induced over-expression of VCAM-1 and ZO-1 disassembly in both atheroprone and atheroprotective areas of mouse aorta, which were reversed by 6′-SL treatment. Altogether, our findings suggest that 6′-SL is a potent therapeutic agent for modulating inflammatory responses and endothelial hyperpermeability.
Purpose Migraine is a highly prevalent headache disorder, and intake of various nutrients and special diets may improve migraine symptoms. We aimed to clarify the association between nutritional status and migraine. Patients and methods We collected the data of 1838/8953 (migraineurs/all participants) from the National Health and Nutrition Examination Survey (NHANES) 1999–2004 cycle. We used weighted multivariable linear or logistic regression analyses to study the association between the prognostic nutritional index (PNI) and the occurrence of severe headache or migraine. Results After adjusting for confounding variables, we found that mild (PNI 45–50) or moderate to severe (PNI <45) malnutrition were associated with higher prevalence of severe headache or migraine (odds ratio [OR] 1.06, 95% confidence interval [CI] 1.00–1.12, P = 0.004; OR 1.07, 95% CI 1.03–1.12, P < 0.001). In addition, we found that those with severe headache or migraine consumed less alcohol, dietary fiber, cholesterol, total folate, vitamin A, riboflavin, vitamin B6, vitamin B12, vitamin C, vitamin K, selenium, potassium, magnesium, and copper, and consumed more caffeine and theobromine than did those without severe headache or migraine. Conclusion The PNI is associated with migraine prevalence, and may thus serve as a predictor of migraine risk and highlights the potential of nutrition-based strategies for migraine prevention and treatment.
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Background: Migraine 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. Objective: The 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. Methods: A 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. Results: A 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. Conclusions: There 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.
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Coffee consumption has been related to a preventive effect against several non-transmissible pathologies. Due to the content of this beverage in phytochemicals and minerals, it has been proposed that its impact on health may partly depend on gut microbiota modulation. Our aim was to explore the interaction among gut microbiota, fecal short chain fatty acids, and health-related parameters in 147 healthy subjects classified according to coffee consumption, to deepen the association of the role of the (poly)phenol and alkaloid content of this beverage. Food daily intake was assessed by an annual food frequency questionnaire (FFQ). Coffee consumption was categorized into three groups: non-coffee-consumers (0–3 mL/day), moderate consumers (3–45 mL/day) and high-coffee consumers (45–500 mL/day). Some relevant groups of the gut microbiota were determined by qPCR, and concentration of fecal short chain fatty acids by gas chromatography. Serum health related biomarkers were determined by standardized methods. Interestingly, a higher level of Bacteroides–Prevotella–Porphyromonas was observed in the high consumers of coffee, who also had lower levels of lipoperoxidation. Two groups of coffee-derived (poly)phenol, methoxyphenols and alkylphenols, and caffeine, among alkaloids, were directly associated with Bacteroides group levels. Thus, regular consumption of coffee appears to be associated with changes in some intestinal microbiota groups in which dietary (poly)phenol and caffeine may play a role.
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The terminology "gut-brain axis "points out a bidirectional relationship between the GI system and the central nervous system (CNS). To date, several researches have shown that migraine is associated with some gastrointestinal (GI) disorders such as Helicobacter pylori (HP) infection, irritable bowel syndrome (IBS), and celiac disease (CD). The present review article aims to discuss the direct and indirect evidence suggesting relationships between migraine and the gut-brain axis. However, the mechanisms explaining how the gut and the brain may interact in patients with migraine are not entirely clear. Studies suggest that this interaction seems to be influenced by multiple factors such as inflammatory mediators (IL-1β, IL-6, IL-8, and TNF-α), gut microbiota profile, neuropeptides and serotonin pathway, stress hormones and nutritional substances. Neuropeptides including CGRP, SP, VIP, NPY are thought to have antimicrobial impact on a variety of the gut bacterial strains and thus speculated to be involved in the bidirectional relationship between the gut and the brain. According to the current knowledge, migraine headache in patients harboring HP might be improved following the bacteria eradication. Migraineurs with long headache history and high headache frequency have a higher chance of being diagnosed with IBS. IBS and migraine share some similarities and can alter gut microflora composition and thereby may affect the gut-brain axis and inflammatory status. Migraine has been also associated with CD and the condition should be searched particularly in patients with migraine with occipital and parieto-occipital calcification at brain neuroimaging. In those patients, gluten-free diet can also be effective in reducing migraine frequency. It has also been proposed that migraine may be improved by dietary approaches with beneficial effects on gut microbiota and gut-brain axis including appropriate consumption of fiber per day, adhering to a low glycemic index diet, supplementation with vitamin D, omega-3 and probiotics as well as weight loss dietary plans for overweight and obese patients.
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Background: The actions of caffeine as an antagonist of adenosine receptors have been extensively studied, and there is no doubt that both daily and sporadic dietary consumption of caffeine has substantial biological effects on the nervous system. Caffeine influences headaches, the migraine syndrome in particular, but how is unclear. Materials and Methods: This is a narrative review based on selected articles from an extensive literature search. The aim of this study is to elucidate and discuss how caffeine may affect the migraine syndrome and discuss the potential pathophysiological pathways involved. Results: Whether caffeine has any significant analgesic and/or prophylactic effect in migraine remains elusive. Neither is it clear whether caffeine withdrawal is an important trigger for migraine. However, withdrawal after chronic exposure of caffeine may cause migraine-like headache and a syndrome similar to that experienced in the prodromal phase of migraine. Sensory hypersensitivity however, does not seem to be a part of the caffeine withdrawal syndrome. Whether it is among migraineurs is unknown. From a modern viewpoint, the traditional vascular explanation of the withdrawal headache is too simplistic and partly not conceivable. Peripheral mechanisms can hardly explain prodromal symptoms and non-headache withdrawal symptoms. Several lines of evidence point at the hypothalamus as a locus where pivotal actions take place. Conclusion: In general, chronic consumption of caffeine seems to increase the burden of migraine, but a protective effect as an acute treatment or in severely affected patients cannot be excluded. Future clinical trials should explore the relationship between caffeine withdrawal and migraine, and investigate the effects of long-term elimination.
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Coffee is a popular beverage throughout the world. Coffee contains various chemical compounds (e.g., caffeine, chlorogenic acids, hydroxyhydroquinone, kahweol, cafestol, and complex chemical mixtures). Caffeine is also the most widely consumed pharmacological substance in the world and is included in various beverages (e.g., coffee, tea, soft drinks, and energy drinks), products containing chocolate, and drugs. The effects of coffee and caffeine on cardiovascular diseases remain controversial. It is well known that there are J-curve-type or U-curve-type associations of coffee consumption with cardiovascular events including myocardial infarction and stroke. However, there is little information on the direct and indirect effects of coffee consumption on endothelial function in humans. It is likely that the coffee paradox or caffeine paradox exists the association of coffee intake with cardiovascular diseases, cardiovascular outcomes, and endothelial function. This review focusses on the effects of coffee and caffeine on endothelial function from molecular mechanisms to clinical perspectives.
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Coffee is one of the most widely consumed beverages in the world and is also a major source of caffeine for most populations [...]
Purpose: We aimed to evaluate the role of caffeinated beverage intake as a potential trigger of migraine headaches on that day or on the following day. Methods: In this prospective cohort study, 101 adults with episodic migraine completed electronic diaries every morning and evening. Ninety-eight participants completed at least 6 weeks of diaries in March 2016-October 2017. Every day, participants reported caffeinated beverage intake, other lifestyle factors, and the timing and characteristics of each migraine headache. We compared a participant's incidence of migraines on days with caffeinated beverage intake to the incidence of migraines among the same individual on days with no intake, accounting for day of week. We used conditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals. Results: Among 98 participants (86 women, 12 men) with mean age 35.1 years, 83% white, and 10% Hispanic or Latino, the average age when headaches started was 16.3 years. In total, the participants reported 825 migraines during 4467 days of observation. There was a statistically significant nonlinear association between the number of caffeinated beverages and the odds of migraine headache occurrence on that day (P-quadratic trend = .024), though estimates for each level of intake were not statistically significant. The associations varied according to habitual intake and oral contraceptive use. Conclusions: There was a nonlinear association between caffeinated beverage intake and the odds of migraine headache occurrence on that day. This suggests that high levels of caffeinated beverage intake may be a trigger of migraine headaches on that day.
Objective To assess the ictal symptoms, interictal symptoms, psychiatric comorbidities, and interictal neuro‐otologic examination findings in vestibular migraine (VM). Methods Retrospective chart review of 491 patients seen from August 2014 until March 2018 at a tertiary neurology referral center for vestibular disorders to identify patients fulfilling the 2012 VM criteria. Results One hundred and thirty‐one patients (105 women) were identified. Mean age of VM onset was 44.3 (±13.7) years. Preceding the onset of vestibular symptoms, most had migraine (57.3%) and motion sickness (61.1%). It was common to have a family history of migraine (50.8%) and episodic vestibular symptoms (28.1%). Common ictal symptoms were triggered (visually induced and head‐motion) and spontaneous vertigo, accompanied by photophobia and phonophobia (118/131 [90.1%] patients), nausea (105/131 [80.2%] patients), aural symptoms (79/131 [60.3%] patients), and headache (65/131 [49.6%] patients). Interictally, many experienced visually induced (116/131 [88.6%] patients), head‐motion (86/131 [65.6%] patients), and persistent (67/131 [51.1%] patients) dizziness. Psychiatric comorbidities include anxiety (92/131 [70.2%] patients), depression (53/131 [40.5%] patients), insomnia (38/131 [29.0%] patients), phobic disorders (15/131 [11.5%] patients), and psychogenic disorders (11/131 [8.4%] patients). Common triggers were stress (52/131 [39.7%] patients), bright lights (35/131 [26.7%] patients), weather changes (34/131 [26.0%] patients), and sleep deprivation (34/131 [26.0%] patients). Interictal neuro‐otologic examination was abnormal in 56/131 (42.7%), usually hyperventilation‐induced, head‐shaking‐induced, vibration‐induced, and positional nystagmus. The most common balance‐test finding was impaired sharpened Romberg’s test (22/130 [16.9%] patients). Conclusions In this single center study, we found that VM typically affects women in their 40s, with a personal and family history of migraine. Typical ictal symptoms were triggered and spontaneous vertigo, associated with photophobia and phonophobia, nausea, aural symptoms, and headache. Interictal vestibular symptoms, comorbid psychiatric disorders, and non‐specific interictal neuro‐otologic findings were common.
Background: The current study was designed to assess the effect of supplementation with a 14-strain probiotic mixture on episodic and chronic migraine characteristics. Methods: Forty episodic and 39 chronic migraine patients who completed this randomized double-blind controlled trial received two capsules of multispecies probiotic or placebo. The migraine severity was assessed by visual analog scale (VAS). The number of abortive drugs consumed, migraine days, frequency and duration of attacks were recorded on paper-based headache diaries. Serum tumor necrosis factor alpha (TNF-α) and C- reactive protein (CRP) levels were measured at baseline and the end of the intervention. Results: After a 10-week intervention, among episodic migraineurs the mean frequency of migraine attacks significantly reduced in the probiotic group compare to the placebo group (mean change: -2.64 vs. 0.06; respectively, p < 0.001). A significant reduction was also evident in the migraine severity (mean decrease: -2.14 in the probiotic group and 0.11 in the placebo group; p < 0.001). Episodic migraineurs who received the probiotic also showed significant reduction in abortive drug usage per week (mean change: -0.72; p < 0.001) compare to baseline, while there was no significant changes within the placebo group. In chronic migraine patients, after an 8-week intervention, the mean frequency of migraine attacks significantly reduced in the probiotic compared to the placebo group (mean change: -9.67 vs. -0.22; p ≤ 0.001). In contrast to the placebo, probiotic supplementation significantly decreased the severity (mean changes: -2.69; p ≤ 0.001), duration (mean changes: -0.59; p ≤ 0.034) of attacks and the number of abortive drugs taken per day (mean changes: -1.02; p < 0.001), in chronic migraine patients. We failed to detect any significant differences in the serum levels of inflammatory markers at the end of the study either in chronic or in episodic migraineurs. Discussion: The results of this study showed that the 14-strain probiotic mixture could be an effective and beneficial supplement to improve migraine headache in both chronic and episodic migraineurs. Further research is required to confirm our observations.