It is well-know that caffeine can stimulate
wakefulness, increase concentration and decrease
the sensation of fatigue, but how does it affect
one of the most common human agonies, headaches?
Caffeine is commonly used as analgesic adjuvant
for the acute treatment of pain. However,
despite the flattering description of the
efficacy above, the general analgesic effect of
caffeine seems at best modest. Besides, chronic
consumption of it may have a flip side,
withdrawal may cause caffeine withdrawal, a
syndrome including symptoms such as drowsiness,
headache, mood-changes, difficulty focusing,
nausea and muscle pain/stiffness. Even small
amounts of caffeine have been shown to suppress
this. Headache can occur independently of the
other symptoms, and Caffeine-withdrawal
headache, properly described in the 1940s, is
recognized as an own diagnostic entity by the
International Classification of Headache
Disorders (ICHD-3). Results from both
experimental and clinical studies indicate a
high rate of caffeine withdrawal in the modern
society, that may even be underestimated. The
real world extent and clinical (physiological
and psychological) importance are not
well-known. The dual effects of caffeine in
headaches, relieving on one side and triggering
on the other side, make caffeine a very
interesting substance in headache
pathophysiology research. Still, the prevailing
theory of the withdrawal headache is basically a
rebound vasodilation due to caffeine's
vasoconstrictive effect, at large a too
simplistic theory that is not in conformity with
modern views of headache pathophysiology. The
caffeine withdrawal syndrome, which includes
symptoms suggestive of the prodromal phase of
migraine, is hardly of peripheral origin. Based
on the current established knowledge on migraine
pathophysiology, this narrative review aims to
explore how caffeine, which has profound
biological effect as an adenosine receptor
antagonist, may influence pathways involved in
headaches, with a particular focus in
migraine.
Yawning Indicates Hypothalamic
Alterations
It has been demonstrated that activating the
A1R on TMN- neurons increases NREM sleep (146),
and that blocking them on hypocretinergic
neurons of the lateral hypothalamus increases
wakefulness (147). Both neurotransmitter systems
have been suggested to play an important role in
migraine (148, 149). The TMN of the posterior
hypothalamus has been suggested to play a role
in the initial phases of a migraine attack and
to be responsible for the morning occurring
migraine attacks (148, 150). During drowsiness
and normal recovery sleep the firing from the
histaminergic neurons are reduced or absent, but
during wakening and arousal they fire, allegedly
the most wake-selective firing pattern
identified to date (151). Adenosine may well
have a protective effect against migraine during
sleep, but during non-recovery sleep and
wakefulness disrupted homeostasis may cause
increased histaminergic firing predisposing for
headaches. It has been postulated that yawning
is the manifestation of a switch in brain states
from "default mode" to an "attentional mode" by
increasing clearance of adenosine (152). It
remains to be proven in experimental models that
increased histaminergic firing sensitizes the
TCC.
Yawning may also be indicative of an
individual's inability to properly maintain
thermal brain homeostasis (153). If yawning
occurs without being associated with tiredness,
it may perhaps indicate a thermoregulatory
dysfunction. In the study of Schoonman et al. of
the premonitory symptoms of migraine there was
no correlation between "sleep problems" and
yawning (Spearman's rank correlation of 0.024)
(65). Further, Jacome described 3 migraineurs
with compulsive yawning as a prodromal symptom,
independent of fatigue and drowsiness (154). In
a recent cross-sectional study, 45.4% of 339
migraineurs reported repetitive yawning during
migraine attacks (155). Sleepiness was
significantly more often reported in patients
with yawning compared to those who did not yawn
during their migraine attacks.
Thermoregulation and sleep are interrelated.
It is well-known that yawning has a clear
circadian pattern parallel to the rise in body
and brain temperature, normally occurring most
often before sleep onset and after waking (153).
A hypothesis that migraine attacks serve to
restore the brain temperature has recently been
put forward (156). In general, the neurons of
the brain are very sensitive to variations in
the temperature (157). Short visual stimulation
of the rat invokes a rise in temperature over
the visual cortex (158), and during prolonged (4
min) visual stimulation in man, an increase in
regional cerebral blood flow caused an average
decrease in temperature by 0.2_C (159).
Histamine has been shown to mainly excite
heat-sensitive neurons in the anterior
hypothalamus, causing hypothermia. In contrast
to adenosine (160), caffeine increase body
temperature parallel to arousal during circadian
misalignment in humans (161). Injecting
neuropeptide orexin-A into the rat PVN elicits a
cortical arousal response followed by yawning
(162), and injecting it into the ventromedial
hypothalamus it induces hyperthermic reactions
(163).
Based on the fact that migraineurs show a
lower threshold for central dopamine receptor
activation than normal subjects (164), and that
exogenously administered dopamine receptor
agonists may produce some symptoms experienced
in the prodromal phase of migraine such as
drowsiness and yawning, dopamine may play an
important role in migraine pathophysiology. This
theory is consistent with the idea that caffeine
withdrawal symptoms are due to increased
sensitivity of adenosine, causing increased
drowsiness (due to increased disinhibition of
VLPO sleep-active neurons reducing histaminergic
tone) and excessive yawning due to increased
dopaminergic tone. It has been shown that
injecting dopamine (D2) agonists into the
paraventricular nucleus of the hypothalamus
(PVN) of rats, increases local nitric oxide (NO)
production and thereby activates central
oxytocinergic neurotransmission, inducing
yawning (165). However, microinjection of other
substances into the PVN, such as histamine (166)
and nitroglycerine (167) also induces yawning.
As distinct from dopamine agonists, that seldom
induces headache (168), both donors of NO and
histamine are established triggers in
pharmacological models of migraine (116).
Glyceryl trinitrate has even been shown to both
induce prodromal symptoms of migraine (169) and
activate the hypothalamus (96).
CONCLUSION
The current opinion is that caffeine both
can relieve and trigger headaches. It has to be
clarified whether caffeine withdrawal triggers
or merely resembles the migraine syndrome. The
nature of the caffeine withdrawal syndrome needs
to be better understood. In assessing the
clinical effects of caffeine withdrawal, there
is a chance that a triggered migraine syndrome
is interpreted as part of the caffeine
withdrawal syndrome, explaining an overlap
between these two. If it triggers migraine
it.
