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mise à jour du
6 janvier 2003
Neurology
1997;49(3):650-6
Migraine
Dopamine and migraine
Peroutka Stephen J
Spectra Biomedical, USA
 
Linking olfaction with nausea and vomiting of pregnancy, recurrent abortion, hyperemesis gravidarum, and migraine headache

Chat-logomini

 
 
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.