Abstract

Background: Nausea is regarded as an essential element in the diagnosis of migraine. However, some patients with migraine do not experience nausea during their migraine attacks. These patients may show different clinical features that demand different management strategies. The authors evaluated how migraineurs without nausea differ from those with nausea in a headache clinic.

Methods: This study enrolled 182 consecutive patients (156 female, 26 male) satisfying the International Classification of Headache Disorders-II criteria of migraine with or without aura from August 2009 to July 2011. Patients who overused medications were excluded. All enrolled patients underwent interviews using a structured questionnaire regarding demographic and clinical features performed by a neurologist specialized in headache disorders.

Results: Of the 182 patients with migraine, 21 never experienced nausea during their migraine attacks (11.5%). These 21 patients were older and experienced a lower frequency of vomiting, osmophobia, and pulsating headache quality (p < 0.05). However, they did not differ from patients who usually suffered from nausea in terms of the presence of an aura, gender, body mass index, headache years, headache severity expressed on a visual analogue scale, Headache Impact Test-6 score, presence of family history, photophobia, or phonophobia.

Conclusions: Migraineurs without nausea showed a tendency to be older and experience less vomiting and osmophobia, and their headache was usually dull and aching rather than pulsating. These results suggest that migraine-associated symptoms have peculiar characteristics that require elucidation by further studies in terms of their clinical significance and role in migraine pathophysiology. 

Background

Methods

We conducted a clinical study on consecutive patients with migraine who newly presented to our headache clinic from August 2009 to July 2011. Migraine was diagnosed on the basis of the diagnostic criteria of the International Classification of Headache Disorders-II (ICHD-II) after a history had been obtained using a semistructured questionnaire and general physical and neurological examinations had been performed. Patients with secondary causes of headache according to appropriate laboratory and/or diagnostic test results were excluded. Patients with migraine and concomitant chronic daily headaches with medication overuse were also excluded. 

All enrolled patients were instructed to answer specific questions to evaluate their migraine characteristics on the basis of their average migraine attacks during the most recent 3 months prior to their first visit. Data on demographic information, headache intensity expressed on a 10-point visual analogue scale (VAS), migraine attack frequency, migraine years, and body mass index were collected. Migraine-associated symptoms such as nausea, vomiting, photophobia, phonophobia, and osmophobia were evaluated in terms of their presence or absence. Migraine-related disability was assessed with the Headache Impact Test-6 (HIT-6) [2]. Patients were questioned again regarding nausea, the main focus of this study, in terms of its absence during all attacks, including those during the most recent 3 months, if the migraineur had answered that nausea was not experienced during his or her attacks.

We conducted a descriptive statistical analysis with SPSS version 18 for Windows (SPSS Inc., Chicago, IL, USA). Numerical data such as age, headache years, VAS score, body mass index, and HIT-6 score were compared between the two groups using a T-test. The χ2 test was used to compare nausea versus other associated symptoms, gender, family history of migraine, aura, headache quality, and headache frequency. All statistical tests were two-tailed, and statistical significance was set at p < 0.05.

Results

A total of 182 patients with newly diagnosed migraine (156 female, 26 male; age, 39.04 ± 15.33 years) were recruited from our headache clinic. Of the 182 patients, 157 had migraine without an aura (MO) and 25 had migraine with an aura (MA). Most of the patients (161/182, 88.5%) reported that they usually experienced nausea during their migraine attacks (MWN), whereas 21 (11.5%) reported that they had never experienced nausea during their migraine attacks (MON). In the demographic profiles, MON patients were older than MWN patients (45.9 ± 16.7 vs. 38.2 ± 15.0, p = 0.03). However, the two groups did not differ in terms of gender ratio or body mass index. Comparison of headache characteristics revealed that the quality of headache, vomiting, and osmophobia were significantly different between MWN and MON patients (Table 1). The MON patients appeared to have a relatively less pulsating headache quality, less vomiting, and less osmophobia compared with MWN patients. There was no significant difference in the presence of aura, migraine years, headache severity, attack frequency, HIT-6 score, or presence of a family history of headache. The presence of photophobia or phonophobia among the associated symptoms of migraine also did not differ between the two groups.We conducted additional analyses to determine whether the differences in the headache quality, osmophobia, and vomiting between the two groups arose from the difference in patient age between the two groups. When we divided the patients into two groups based on the age of 60 years, the variables that had shown significance in the analysis conducted for all patients (headache quality, vomiting, and osmophobia) were not significantly different in the patients older than 60 years. On the contrary, 158 patients younger than 60 years still showed significant differences in these variables (Table 2). Phonophobia was more common in MON patients (93.3% vs. 67.8%, p = 0.04).    

Discussion

Nausea is a main symptom that most patients with migraine experience during their migraine attacks. Nausea reportedly affected 73% of patients with migraine in a population-based study [3]. In another study, about half (49.5%) of the patients with episodic migraine experienced frequent nausea (half of the time or more), and 21.4% experienced nausea less than half of the time [1]. The proportion of patients with migraine who experienced nausea during their migraine attack was even higher in a clinic-based study (about 90%) [4]. This is very similar to the result of our study (88.5%). The high frequency of nausea as an associated symptom of migraine necessitates its inclusion as an important diagnostic criteria of migraine.

Nausea is generally described as an unpleasant wave-like sensation in the throat, epigastrium, or abdomen that often precedes but does not always culminate in vomiting [5]. The nucleus tractus solitarius (NTS) in the brain stem receives converging visceral, spinal, and trigeminal nociceptive inputs and is critically involved in medullary reflexes controlling cardiovascular, respiratory, and gastrointestinal functions [6]. Upon the convergence of these various inputs, the NTS develops vagal (nausea, vomiting, and inhibitory cardiac responses), sympathetic (sweating and excitatory cardiac responses), and motor responses (abdominal muscle contraction). That is, nausea as a migraine-associated symptom is based on the connection between the NTS and trigeminal nociceptive system.

In our study, migraineurs without nausea were older and showed a tendency to have a less pulsating quality, less vomiting, and less osmophobia than those with nausea.

Among the variables showing statistical significance, age must be interpreted cautiously. The frequency and intensity of migraine attacks as well as the migraine-associated symptoms have a tendency to decrease with age in adults [7]. In addition, the intensity and pulsatile quality of headaches were reportedly associated with the presence of migraine-associated symptoms such as nausea, vomiting, photophobia, and phonophobia in a previous report [4]. Considering these findings, there is a possibility that the disability experienced by older migraineurs is less severe than that experienced by younger migraineurs. Because symptoms usually considered diagnostic for migraine (nausea and/or vomiting and phonophobia) were significantly associated with prolonged and severe pain in this study, we can speculate that the absence of nausea in older migraineurs results from less disability with such a background. Furthermore, high-frequency migraine-associated nausea was reported to be a marker for severe, debilitating migraine [1]. In this study, however, the intensity, frequency, and degree of disability evaluated with the HIT-6 between the two groups were not statistically different, indicating that the difference in age between the two groups did not cause any differences in disability or intensity.

Nonetheless, we reevaluated whether any differences existed between the MWN and MON groups after dividing the migraineurs into two age groups based on the age of 60 years. Although dividing the patients according to the age of 60 years is somewhat arbitrary, it is thought that age results in the decline in estrogen after menopause in women, who comprised the majority of the study patients [8]. In general, migraine-associated symptoms are known to decrease and “probable migraine,” according to the ICHD-II, are known to increase with age after a patient passes their 30s [9]. In that sense, the age difference between the MWN and MON groups may introduce bias and should be corrected.

Our analysis of the two different age groups revealed that headache quality, vomiting, and osmophobia, which were statistically significant variables in the analysis of all migraineurs, remained significant, at least in the younger age group.

The finding that nausea and vomiting are correlated is expected. Vomiting not preceded by nausea is not thought to be probable.

The pulsatile quality of a headache is caused by vasodilation of the pain-sensitive large cranial vessels and dura mater. Trigeminal nociceptive activity is processed through two pathways, the trigeminal parasympathetic reflex and neurogenic inflammatory process, that involve the release of neuropeptides such as calcitonin gene-related peptide from trigeminal nerve terminals [10]. The trigeminal nucleus caudalis and NTS lie in the center of this process and have neuroanatomical proximity or specific neuroanatomical connection, which implies the close association of nausea and the pulsatile quality of migraine [11].

Interestingly, osmophobia was substantially more prevalent in MWN patients (42.4%) than in MON patients (4.3%). Osmophobia refers to an unbearable perception of odors that are nonaversive or even pleasurable outside the attacks [12, 13] and is a migraine-specific symptom. In a previous report, osmophobia was experienced during attacks in 25% to 43% of patients with migraine [13, 14] in contrast to 0% of patients with tension-type headache [13]. It was also more common in female than in male patients [14]. Another study investigating the prevalence of osmophobia in juvenile patients with headache reported that 25.1% of patients with migraine experienced osmophobia [15]. The specificity of osmophobia for the differential diagnosis of migraine and tension-type headache was greater than that of photophobia or phonophobia among possible associated symptoms. With this background, the adoption of osmophobia as a diagnostic criterion of migraine is thought to be reasonable and is awaiting validation.

However, the finding that only osmophobia was correlated with nausea among migraine-associated symptoms is noteworthy. The observed relationship between osmophobia and nausea in our study may be another example of the link between headache disability and associated symptoms. A recent report that osmophobia was better correlated with headache duration than headache intensity suggests the same implication [4].

In terms of the relationship between olfaction and nausea, hyperacuity of the olfactory system induced by rapidly increasing estrogen concentrations during early pregnancy may be an important contributing factor to nausea [16]. One study of a small sample of women with congenital anosmia suggested that olfaction is a highly selected trigger for nausea and vomiting of pregnancy [17]. Furthermore, the 20-fold frequency of hyperemesis in women with migraine headache compared with control subjects and the 2-fold increase in patients with hyperemesis experiencing migraine headache [18] suggest a similar relationship between olfaction and nausea in patients with migraine. A recent study investigating the patterns of odor-induced migraine in women also showed that the most frequently reported symptom in patients with olfactory-sensitive migraine was nausea [19]. In spite of the lack of precise knowledge about the involved anatomical pathway, there is no doubt that functionally, olfaction and nausea are intimately interconnected.

It is well known that nausea in patients with migraine is a dopamine-related symptom and serves as an example of the role of dopamine in the pathogenesis of migraine [20]. Other evidence of the role of dopamine in migraine include premonitory symptoms such as yawning, drowsiness, and mood changes, which imply dopamine hypersensitivity [21]. The results of clinical trials on the effect of various dopamine antagonists, especially D2 receptor antagonists, on the alleviation of migraine-associated symptoms in the acute treatment of migraine [22, 23] could have similar meanings under such a background. This dopamine hypersensitivity is believed to be genetic, caused by a polymorphism in the gene encoding the dopamine D2 receptor (DRD2) [24] and/or dopamine-β-hydroxylase [25]. Osmophobia may also be dopaminergic in its origin. Evidence suggests a role of dopamine in olfactory processing. Transgenic mice lacking the dopamine transporter or the DRD2 receptor showed a deficit in olfactory discrimination [26], and rats injected with L-DOPA outperformed controls in odor discrimination in a dose-dependent manner [27]. It is well known that at least 90% of patients with Parkinson’s disease have smell dysfunction [28]. The prevalence of migraine among patients with Parkinson’s disease is reportedly lower than that of otherwise healthy controls with lifetime migraine [29].

The authors believe that this correlation could be regarded as being in the same “module” in the pathophysiology of migraine. In the “modular headache theory,” there are at least three migraine modules: one each for throbbing pain, photo/phonophobia, and nausea [11]. Nausea and osmophobia may share the same role through the NTS in migraine attacks. This assumption requires elucidation through further basic experimental studies.

This study has some limitations due to the small size of the study population and the different sizes of the groups studied. Considering the rarity of migraineurs without nausea, any study on these patients will require more time or more centers to gather adequate data. The different result from the recent population-based study that nausea did not reflect the disability could be interpreted as the difference in study population. One clear strength of the study is that the patients were investigated by face-to-face interview so that information about their migraine features would be more accurate than that obtained by self-report questionnaires.

Conclusion

The authors believe that migraineurs without nausea have different clinical features necessitating a different approach to management, especially in regard to the dopaminergic system.

Competing interests

The authors declare that there are no competing interests.

Authors' contributions

JC conceived of this study and drafted the manuscript. KP contributed to the study design and the analysis and interpretation of data. JK participated in critical conceptual development and revision of the manuscript.

Acknowledgement

This work was supported by the Inje Research and Scholarship Foundation in 2011.

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Source(s) of Funding

None

Competing Interests

The authors declare that there are no competing interests.