Recent scientific and clinical interest, in
migraine has focused on the pathophysiologic
role of 5-hydroxytryptamine (5-HT) and
neuropeptides. However, dopaminergic systems
also appear to play a major yet less recognized
role in the disorder. Indeed, Sicuteri proposed
that a dopaminergie hypersensitivity exists in
migraine in 1977. Lance pointed out that since
nausea often precedes the headache, then changes
in brainstem dopaminergic neurotransmission must
be part of an attack. A variety of dopamine
antagonists are effective in the acute treatment
of migraine. However, the utility of dopamine
antagonists bas almost always been attributed to
their antiemetic, sedative, or gastric motility
effects rather than to a specific antimigraine
effect. As described in this review, a growing
body of data indicates that dopaminergie
activation is a primary pathophysiologic
component in certain subtypes of migraine.
Evidence for activation of dopaminergie
receptors in migraine. A variety of
prodromal symptoms is often noted by a
migraineur in the days or hours prior to
headache onset. For example, yawning,
drowsiness, mood changes, irritability, and
hyperactivity have been reported to precede or
accompany a migraine attack in 7 to 10% of
migraineurs. However, with the exception of
yawning, these symptoms are difficult to
quantitate.
Therefore, it is of interest to note that
the administration of very low doses of the
dopamine agonist apomorphine (5 µg/kg or
approximately 1% of the dose that improves
Parkinson's disease) induced a significantly
higher number of yawns in migraineurs than
in an age-matched control group. Similar results
were obtained in an independent, double-blind,
placebo-controlled study in which apomorphine
(0.25 mg) induced a significantly higher number
of yawns (p < 0.01) in migraineurs than in a
control group.111 Moderate or severe headache
was also induced in 86% of the migraineurs but
in none of the control group in this apomorphine
study. The increased sensitivity of migraineurs
to apomorphine are consistent with the
hypothesis that a central hypersensitivity to
dopaminergic stimulation exists in
migraineurs.
Yawning is a behavior that has been
linked to activation of dopaminergic
neurotransmission. In rats, yawning can be
elicited by relatively low doses of D2, but not
Dl, receptor agonists. The D2induced yawning is
blocked by both Dl and D2 antagonists,
suggesting that a functional relationship
between Dl and D2 receptors must exist. A
central site of action was proposed since the
peripheral D2 antagonist, domperidone, did not
block the induced yawning. Thus, yawning bas
been proposed to be a behavioral correlate of
increased dopaminergic neurotransmission.
Higher doses of dopaminergie agonists in
both humans and animals induce hyperactivity and
irritability. Indeed, mood fluctuations,
irritability, and sleep disturbances are
well-known side effects of dopamine agonists
such as bromocriptine and pergolide, which are
used to treat Parkinson's disease.
Nausea and vomiting. Nausea and/or
vomiting are the most common nonpainful clinical
features of migraine, both during the headache
phase as well as during the prodromal phase.
Nausea is reported as a component of migraine by
more than 80% of patients, and vomiting occurs
at least occasionally in as many as 50% of
patients. Indeed, the presence of nausea and/or
vomiting are key criteria required for the
diagnosis of migraine established by the
International Headache Society. The unequivocal
efficacy of dopaminergic antagonists for these
symptoms indicates that dopamine receptor
stimulation occurs during the evolution of the
migraine attack. Moreover, clinically effective
antiemetic dosages correlate with their affinity
for dopamine D2 receptors, suggesting that D2
receptor activation is likely to be involved in
the pathogenesis of migraine-associated nausea
and vomiting.
Gastrokinetic changes. Gastrokinetic
dysfunction has been documented during a
migraine attack. Compared with normal controls
as well as with nonmigrainous periods,
significant impairment of aspirin absorption
occurred during a migraine attack. Radiologie
studies of migraineurs demonstrate delayed
gastric emptying during an attack but not
between attacks. Metoclopramide, a dopamine
antagonist, restored normal gastric function and
absorption, an effect attributed to its ability
to accelerate gastrointestinal (GI) motility and
gastric emptying. Therefore, dopaminergic
hyperactivity in the GI tract may lead to
suboptimal oral drug absorption.
Hypotension. Migraine has been
associated with hypotension and occasionally
with syncope. In addition, migraineurs have been
reported to have exaggerated BP responses to a
number of dopamine agonists. For example, 2.5 mg
bromocriptine given to normotensive individuals
induced an intense hypotensive reaction in
migraineurs (N = 18), but not in a contro group.
The most significant diffeerence (P < 0.001)
between the two groups was in the systolic BP
measured 2 hours alter bromocriptine
administration. In a small study of migraineurs
with syncope, migraineurs without syncope, and a
control group, a dose of 2.5 mg bromocriptine
induced the most significant BP changes in the
migraineurs with syncope. Interestingly, a
peripheral dopamine antagonist, domperidone,
counteracted the hypotension and nausea induced
by bromocriptine. In a recent patient report,
a very low dose of apomorphine (0.37 mg) induced
nausea, perspiration, yawning, and epigastric
distress followed by headache and vomiting and
subsequent syncope in a 22-year-old
migraineur.
The anatomic location of peripheral dopamine
receptors may provide insights into the
mechanism by which dopaminergic stimulation
induces hypotension. Dopamine receptors are
located on presynaptic noradrenergic sympathetic
ganglia, where they act to inhibit the release
from the sympathetic nerve terminals. It has
been postulated that a hyperresponsiveness of
these dopamine receptors leads to excessive
inhibition of norepinephrine release, resulting
in the hypotension and syncope associated with
migraine. This conclusion is also supported by
studies using another dopamine
agonist-piribedil. Piribedil increased cerebral
blood flow, decreased BP, and induced nausea in
migraineurs at doses that had no significant
effect in a control group. Domperidone blocked
both the induced nausea and hypotension, again
suggesting a peripheral dopamine receptor
hypersensitivity. In a larger study, an
intravenous infusion of 0.1 mg/kg piribedil
induced nausea and vomiting in 94% of
individuais and hypotension severe enougli to
discontinue the infusion in 69% of migraineurs,
but had only minimal effects in control
subjects. Piribidel-induced hypotension and
nausea in inigraineurs with severe, refractory
migraine with aura (MWA) lias been reported by
an independent group of investigators.
Neuroendocrinologic changes. A
dopaminergic receptor supersensitivity in
migraineurs has also been demonstrated in
neuroendocrinologic studies. For example,
menstrual variations in the control of prolactin
secretion exist in migraineurs versus controls.
In another study, deprenyl (5 mg) was
significantly more effective in reducing
prolactin levels in migraineurs compared with
controls. The effect was more pronounced in MWA
than migraine without aura (MO). The
differential sensitivity to dopaminergic
stimulation was attributed to dopamine receptor
supersensitivity in migraine.
Headache. In general, headache is not
a common, recognized side effect of direct
dopamine agonists used in the treatment of
Parkinson's disease. However, low-dose
apomorphine (1 mg) has been reported to induce
migrainous headaches in elderly individuals with
a past history of migraine who were undergoing
treatment for Parkinson's disease. As mentioned,
a very low dose of apomorphine (0.37 mg) has
been reported to induce a migraine attack in a
22-year-old migraineur.
Dyskinesias. Hyperkinetic movement
disorders are a well-known sign of increased
dopaminergic activity. In a number of anecdotal
reports, dyskinesias have been described in
association with a migraine attack. Numerous
case reports of movement disorders in migraine
have been reviewed, and the term hemicrania
choreatica has been proposed to describe this
phenomenon. The authors cautioned that "jumping
to the conclusion" that both migraine and chorea
share dopamine as their pathophysiologic basis
was "speculation, no more than that ." However,
the fact that dyskinesias have been reported
during a migraine attack represents additional
data to support the role of dopamine in the
pathophysiology of migraine.
Other. Blood flow velocity in the
middle cerebral artery has been measured in
migraineurs and controls using transcranial
Doppler monitoring. Following low-dose
apomorphine administration (5 and 10 ~Lg/kg)
systolic velocity and mean velocity
significantly increased, and the pulsatility
index decreased in migraineurs compared with
control subjects. Dopamine receptors have been
located directly in vascular beds (e.g., on
cerebral arteries) -that are believed to be
involved in the-pathogenesis of migraine. For
example, dopamine receptors have been localized
to pial vessels, the site of neurogenic
inflammation that has been suggested to play a
role in the headache component of migraine. Once
again the ability of low-dose apomorphine
administration to alter cerebral blood flow in
migraineurs compared with control subjects was
interpreted to indicate that migraineurs have an
increased sensitivity to dopaminergic
stimulation.
Dopamine antagonists as therapeutic
agents in migraine. As pointed out by Raskin
many of the drugs used in the treatment of
migraine have been used for empirical reasons or
for actions that subsequently have been shown to
be unrelated to migraine pathophysiology. The
use of antiemetics appears to be in this
category. Perhaps the most compelling clinical
confirmation of the hypothesis that relative
hyperactivity of dopaminergic neurotransmission
occurs (in at least a subset) of migraineurs is
the fact that blockade of D2 dopamine receptors
(DRD2s) has been shown to relieve acutely many
of the symptoms of a migraine attack. Indeed, a
significant amount of data exists to support the
efficacy of DRD2 antagonists in the acute
treatment of migraine that extends far beyond
the relief of nausea and/or voiniting. lt should
be noted that the studies summarized here were
performed by multiple investigators using a
variety of diagnostic criteria and clinical end
points to assess drug efficacy. More formal
placebo-controlled, double-blind studies are
needed to determine most accurately the efficacy
of dopamine antagonists in the acute treatment
of migraine.
Haloperidol. Haloperidol is a potent
DRD2 antagonist that lias been reported to have
antiemetic activity. In a recent small study,
haloperidol (5 mg IV) completely or
substantially relieved headache in six of six
patients within 25 to 65 minutes after
administration. Side effects were reported to be
minimal or nonexistent, and there was no
apparent recurrence of the headache. The authors
suggested that the emergency room use of
haloperidol in acute migraine attacks might be
an effective, readily available, and
cost-effective therapeutic approach that
deserves more formal clinical study.
Prochlorperazine. Prochlorperazine is
another potent DRD2 antagonist that has
demonstrated a high degree of efficacy (82 to
88%) in the acute treatment of migraine. In a
prospective, randomized, double-blind cliiiical
trial of prochlorperazine (10 mg IV), 74% of
patients (31 of 42) had complete relief and an
additional 14% (six of 42) had partial relief
within 60 minutes of administration. The drug
was significantly more effective (p < 0.0001)
than placebo, and adverse events were reported
to be minimal (one patient experienced
asymptomatic orthostatic hypotension). The
patients who experienced complete relief of
headache did so, on average, within 21 minutes
of drug administration. The authors concluded
that IV prochlorperazine is an effective
treatinent for migraine. In a second
prospective, randomized, double-blind,
placebo-controlled clinical trail
prochlorperazine (10 mg IV) was reported to be
effective within 30 minutes in 82% (18 of 22) of
the patients. No recurrence of headache was
observed in the first 24 hours after treatment.
The drug was significantly more effective (p
< 0.001) than placebo, and adverse events
consisted of two dystonic reactions. The authors
concluded that IV prochlorperazine reduces both
the headache and nausea associated with an acute
migraine attack .
Domperidone. Domperidone is a
moderately potent DRD2 antagonist. However,
domperidone penetrates the blood-brain barrier
poorly, so it is considered a peripheral DRD2
antagonist. Interestingly, domperidone has been
shown to prevent the occurrence of migraine if
taken during the prodromal phase of the
disorder. In a placebo-controlled, double-blind
study, domperidone (30 mg) prevented an attack
of migraine in 66% versus 5% of placebotreated
patients (p < 0.001) if taken hours before
the predicted onset of the headache. The fact
that oral domperidone, if taken prior to the
aura, can prevent the occurrence of a migraine
attack provides additional, strong support for
the hypothesis that dopaminergic
neurotransmission plays a key role in the
pathogenesis of an attack of migraine. In an
independent study oral domperidone shortened the
duration of a migraine attack and had no
associated adverse events. The fact that
domperidone poorly penetrates the CNS indicates
that a significant amount of migraine
symptomatology results from the activation of
peripheral dopamine receptors.
Chlorpromazine. Chlorpromazine is
slightly less potent than haloperidol,
prochlorperazine, and domperidone at the DRD2
receptor but bas been used at relatively higher
doses in the acute treatment of migraine.
Intravenous chlorpromazine is reported to be
effective in 89 to 94% of migraine patients
treated in an emergency department.Moderate
drowsiness is a common side effect. Similarly,
IM chlorpromazine (1 mg/kg) relieved both the
headache and associated nausea/vomiting in 96%
of migraine patients treated in an emergency
department (N = 100), although transient
orthostatic hypotension was included in 18%.
Patients who obtained relief did so, on average,
35 minutes after drug administration. In a study
where some relief of migraine symptoms occurred
in 84% of individuals treated with IM
chlorpromazine, the authors noted that the drug
was "considerably more effective in those
patients whose symptoms more closely approximate
'classical' migraine". These data indicate that
chlorpromazine is an effective agent for the
acute treatment of migraine.
Flunarizine. Flunarizine, initially
developed as a calcium channel blocker, has also
been reported to be effective in both the acute
and prophylactic treatment of migraine.
Flunarizine displays significant dopamine
antagonist properties and a moderately high
affinity for the DRD2 receptor. In two
independent studies IV flunarizine (20 mg)
provided 74 to 78% relief in the acute treatment
of migraine, with the highest response rate
observed in patients with "elassical
migraine".
Metoclopramide. Metoclopramide, a
nonphenothiazine DRD2 antagonist with a
relatively low affinity for the D2 receptor, has
also been studied extensively in the treatment
of migraine. The use of metoclopramide in
migraine is common in Europe, where it is
usually considered an adjunct medication that
improves absorption of concurrent oral
analgesics. However, IV metoclopramide alone (1
to 10 mg) has shown a positive effect in
multiple independent studies. In addition,
metoclopramide bas been shown to have "a
definite beneficial effect when given
prophylactically (10 mg orally three times per
day) to individuals with migraine .The more
moderate efficacy of metoclopramide compared
with the other DRD2 antagonists in oral studies
is consistent with its relatively low affinity
for the DRD2 receptor.
Combination therapies using dopamine
antagonists in migraine. Nearly all experienced
clinicians have recommended the use of dopamine
antagonists in combination with other agents in
the treatment of migraine. For example, the
protocols developed by Callaham and Raskin
included in the use of a dopamine antagonist
prior to ergot injection. Likewise, the use of
dopamine antagonists for individuals with severe
nausea and/or vomiting is common in clinical
practice. Most recently an oral combination of
metoclopramide (10 mg) and lysine
acetylsalicylate (equivalent to 900 mg ASA) was
equivalent to 100 mg suinatriptan and
significantly better than placebo (p <
0.0001) in relieving an acute migraine
attack.
Genetic data. Molecular genetics
offers a novel approach to the understanding and
management of migraine since the disorder is
known to have a strong genetic component. In a
recent study, a Nocardia corallina-1 (Nco1)
polymorphism in the gene encoding DRD2 was
evaluated in a group of 250 unrelated
individuals. The major finding of the study was
that susceptibility to MWA is modified by DRD2
Nco1 alleles. The presence of the DRD2
Nécol1 A1 allele has a significant effect
on susceptibility to MWA conipared with a
control group of nonmigraineurs as well as with
individuals with MO. However, A is also clear
that since not all individuals with the DRD2
Nco1A1A1 genotype suffer from MWA, multiple
additional genes are involved in the
pathogenesis of migraine. Thus, the DRD2 Nco1 A1
allele is neither necessary nor sufficient to
cause MWA. However, since molecular variations
within the DRD2 gene have been associated with
variations in dopaminergic function these data
suggest that alterations in dopaminergic
neurotransmission can modulate the clinical
susceptibility to MWA. Therefore, these data
provide molecular genetic support for the
hypothesis that the pathophysiologie basis of
migraine can be modified by variations in DRD2
function.
Conclusions. The data summarized in
this review provide strong support for the
hypothesis that increased dopaminergic activity
is a key pathophysiologic component of migraine.
These data support the hypothesis that at least
in a large subgroup of migraineurs, dopamine
acts as an endogenous proagonist in the
pathophysiology of the disorder. Antagonism of
this protagonist neurotransmitter therefore
results in symptomatic relief of both the
headache and associated symptoms. However,
despite the considerable data that support their
use in migraine, a scientific basis for the
standard use of dopamine antagonists in migraine
has not yet been established.
By contrast, current therapeutic approaches
are focused on stimulating 5-HT1 receptors.
5-Hydroxytryptamine appears to act as the
endogenous antagonist in the pathophysiology of
migraine, since drugs that stimulate 5-HT1
receptors provide only transient symptomatic
relief of the disorder. Migraine symptoms return
in approximately half of individuals treated
with the 5-HT1 agonist sumatriptan. Moreover,
sumatriptan given during the aura does not
prevent or delay headache development. By
contrast, antagonists of the putative
protagonist neurotransmitter dopamine can be
used effectively before the aura and appear to
be associated with no or minimal headache
recurrence.
A growing body of biological, pharmacologic,
and genetic data indicate that activation of
dopaminergic neurotransmission is a major
pathophysiologie component of migraine. The
efficacy of dopamine antagonists in the acute
treatment of migraine can be attributed to the
blockade of this key pathophysiologie component,
in addition to their known antiemetic and
gastrointestinal motility effects. As a result,
the data summarized in this report support the
routine use of dopamine antagonists as
first-line agents in the acute treatment of
migraine.
Linking
olfaction with nausea and vomiting of pregnancy,
recurrent abortion, hyperemesis gravidarum, and
migraine headache.
Heinrichs L
Headache 2003
Mar;43(3):304-5
Am J Obstet Gynecol. 2002 May;185(5
Suppl Understanding):S215-S219
OBJECTIVE: The experience of women
was sought about nausea and vomiting, its
relation to olfaction, its occurrence among
pregnant women with anosmia, and the potential
association of hyperemesis gravidarum and
migraine headache.
METHODS: We performed a
community-based study with a
physician/patient-directed questionnaire, and a
retrospective analysis of hospital records.
RESULTS: Nearly all women (n = 163
parous women) experience nausea (98%) and
vomiting (97%). The highest frequency causes of
nausea and vomiting were "food poisoning" (65%),
"flu" (58%), pregnancy (54%), and offensive
odors (52%); vomiting occurred as frequently as
nausea for the first 2 causes, and one half as
often for the latter causes. Most women reported
that the pain experienced during vomiting
exceeded that of parturition. Among 9 women with
hypogonadotropic anosmia with advanced
reproductive technology-induced pregnancies, 2
experienced nausea and vomiting, one from "food
poisoning." Among 37 women with migraine
headache, 10 (27%) had experienced hyperemesis
gravidarum, and among 16 who experienced
hyperemesis gravidarum, 5 (37%) had migraine
headaches.
CONCLUSIONS: The frequency of nausea
and vomiting, caused most often by
nonpregnancy-related triggers, is high among
women. In a small sample of women with
congenital anosmia, nausea and vomiting of
pregnancy occurred in only 1 pregnancy,
suggesting that olfaction is a highly selected
trigger for nausea and vomiting of pregnancy.
The shared nausea and vomiting experience of
hyperemesis gravidarum and migraine headache
among women suggests a common mechanism,
possibly based on allelic variations within the
DRD2 (dopaminergic receptor) gene. Because
olfactory receptors, odor types, and MHC
antigens are closely integrated, and because
olfactory stimuli often incite episodes of
pregnancy, nausea, and vomiting, hyperemesis
gravidarum, and migraine headache, these genes
and their products invite further scrutiny. The
pregnancy-conserving effect of PNV and the MHC
antigen overlap in couples with recurrent
abortion are important clues possibly relating
olfaction, MHC antigens, and reproductive
success or failure. Comment: Dr Stephen Peroutka
described a group of patients with migraine with
DRD2 gene abnormalities that he thought might
predict for antidopamine medication efficacy in
treating their migraines. He felt these patients
had prominent dopaminergic manifestations in
their migraine presentations: yawning and severe
nausea and vomiting. (Peroutka SJ. Dopamine and
migraine. Neurology. 1997;49:650-656). The
current study suggests that we may be able to
look for other comorbid illnesses, such as
hyperemesis gravidarum, to find patients with
"dopaminergic migraine," if this entity
exists.
