HEADACHE & FACIAL PAIN SECTION. Migraine, Osmophobia, and Anxiety. Original Research Article

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1 Pain Medicine 2016; 17: doi: /pm/pnv071 HEADACHE & FACIAL PAIN SECTION Original Research Article Migraine, Osmophobia, and Anxiety Pedro Augusto Sampaio Rocha-Filho, MD, PhD,*, Karine Sobral Marques, Medical Student,* Rinailda Cascia Santos Torres, Medical Student,*, and Kamila Nazare Ribas Leal, Medical Student*, *Universidade de Pernambuco, Recife, PE, Brazil; Department of Neuropsychiatry, Universidade Federal de Pernambuco, Recife, PE, Brazil; Scientific Initiation Fellowships Institutional Program (CNPq) Correspondence to: Pedro Augusto Sampaio Rocha Filho, MD, PhD, Rua General Joaquim Inacio, 830, Sala Edf The Plaza Business Center CEP, Recife PE, Brazil. Tel: þ ; Fax: þ ; pasrf@ig.com.br. Conflicts of interest: There are no conflicts of interest to report. Abstract Objectives. To evaluate the association between osmophobia and the characteristics of patients and their headaches, among migraine patients. Methods. This was a cross-sectional study. Patients who consecutively sought medical attendance in a primary care unit were asked about their headaches over the last 12 months. Those who had migraine were included. A semi-structured interview, the Headache Impact Test and the Hospital Anxiety and Depression Scale were used. Results. 147 patients had migraine; 78 had osmophobia; 60 had significant anxiety symptoms; and 78 had significant depression symptoms. The mean age of these patients was 43.2 years (6 13.7); 91.2% were women. The mean length of time with complaints of headache was 13.8 years (6 12). Among the migraine patients, those with anxiety, more years of headache history, and phonophobia presented significantly more osmophobia (multivariate logistic regression). Conclusion: Osmophobia in migraine patients is associated with significant anxiety symptoms, length of headache history, and phonophobia. Key Words. Migraine Disorders; Odors; Osmophobia; Anxiety; Affective Symptoms; Limbic System Introduction Osmophobia is defined as intolerance to odors. The prevalence of osmophobia ranges from 25 86% among adult migraineurs [1 11] and from 25 35% among children and adolescents with migraine [12,13]. Migraineurs may have increased sensitivity to odors even between headache attacks [14]. Few studies have evaluated the association between osmophobia and the characteristics of patients and their headaches among migraine patients. Most of these studies have been conducted in tertiary-level headache outpatient clinics, and this has compromised their capacity for generalization. Women [2,4], individuals with pulsatile pain, patients whose headaches worsen through physical exercise, those with photophobia or phonophobia [2], and those with anxiety symptoms [2,15] have higher chances of presenting osmophobia among adults with migraine [2]. The duration of the pain [5] and intensity of the crisis [5,15] are also related to the presence of osmophobia. The first part of this research has already been published. We studied osmophobia in patients with any kind of headache and the usefulness of osmophobia for diagnosing migraine. We found high prevalence of osmophobia among migraine patients, and this complaint was useful in making the diagnosis of migraine within primary care. Osmophobia was associated with migraine and length of history of any kind of headache [9]. In that first article, we did not explore the association between osmophobia and migrainous patients characteristics because many of these characteristics are part of the diagnostic criteria for migraine. A better understanding of the relationship between osmophobia and other migraine characteristics could deliver better understanding about migraine physiopathology. The aim of the present study was to evaluate the association between osmophobia and characteristics of patients and their headaches among migraine patients. Methods Setting This was a cross-sectional study conducted at the Alto do Maracana primary care unit in the city of Recife, VC 2015 American Academy of Pain Medicine. All rights reserved. For permissions, please journals.permissions@oup.com 776

2 Migraine, Osmophobia, and Anxiety Brazil. Primary care units in Brazil are responsible for providing outpatient care for diseases that are more common and less complex. These are units with family doctors who usually are the first resource for people who seek medical assistance. Headaches are among the most frequent causes of attendance [16]. Data Collection Patients who consecutively sought medical attendance for several reasons were asked about headaches over the last 12 months. Those who reported having had at least one episode of headache during the last 12 months answered a specific semi-structured questionnaire. This questionnaire sought sociodemographic data and information on the characteristics of the headaches and intensity of headaches (on a nominal analogue scale from 1 to 10, with 1 meaning very low pain intensity and 10 meaning very high). The interviews were carried out between January and August Osmophobia during the headache crisis was defined as intolerance to odors that generally leads to avoiding them. These odors are not disagreeable when the patient does not have a headache. The headaches were classified in accordance with the diagnostic criteria established by the third edition of the International Classification of Headache Disorders (ICHD-3 beta) [17]. Three medical students (KLM, RCST, and KNRL) conducted the interviews. Dr. Rocha Filho, a neurologist with experience in treating headaches, checked the diagnosis. If there were any difference in the diagnoses, the diagnosis of the neurologist prevailed. The diagnoses were based on headache characteristics. No physical examination or brain imaging was done by the researchers. The patients were examined by family doctors. The Headache Impact Test (HIT-6) was used [18]. The scores in this questionnaire range from 36 to 78 points. The higher the HIT-6 score is, the higher the impact of the headache is [18]. The Brazilian version of the Hospital Anxiety and Depression Scale (HADS) was applied [19]. Individuals with eight or more points on the anxiety scale were classified as having anxiety. Individuals with eight or more points on the depression scale were classified as having depression [20]. HADS was found to perform well in assessing the symptom severity and caseness of anxiety disorders and depression in both somatic, psychiatric, and primary care patients and in the general population. This scale is not able to perform the specific diagnosis of anxious and depressive disorders such dysthymia, major depressive disorder, dysthymia, or phobias [20]. Statistical Analysis The statistical analysis was carried out using STATA, version 12.0 [21]. All statistical tests were two-tailed, and significance was based on an alpha of The descriptive analysis included absolute values, percentages, averages, and standard deviations (SD). Categorical variables were compared across groups using Fisher s exact test or the Yates chi-square test. For numerical variables, the nonparametric Mann- Whitney test was used [22]. Multivariate logistic regression models with a forward stepwise selection process were used for osmophobia. Variables for which the P value was less than 0.2 in the univariate analysis were considered for inclusion in the model. Those for which the P value remained less than 0.1 were kept in the model [22]. Ethical Considerations All patients gave their informed consent. The study was approved by the Research Ethics Committee of the Oswaldo Cruz University Hospital (number ). Results Three hundred twenty-two patients sought the primary care unit, of whom 147 had migraine and were thus included in the study. No patient had any disease that could modify olfaction. No patients were identified as having secondary headache, from the medical consultation. Twenty-five sought medical assistance for headache. Sixty patients had anxiety and 78 patients had depression. The mean age of these patients was 43.2 years (standard deviation, SD ¼ 13.7); 91.2% were women; and the mean schooling level was 8.3 years (SD ¼ 3.9). The mean length of time with complaints of headache was 13.8 years (SD ¼ 12); the mean frequency of headaches was 32 days with headaches over a three-month period (SD ¼ 24); the mean intensity of the headaches was 8.2 (SD ¼ 1.8); the mean score in the Headache Impact Test was 62.1 (SD ¼ 11.3). Seventy-eight patients had osmophobia. Table 1 shows the associations between the sociodemographic variables, headache characteristics, and presence of osmophobia among those with migraine. The older individuals and those with anxiety, greater impact from headaches, auras, and phonophobia presented significantly more osmophobia. Table 2 shows the results from the multivariate logistic regression for osmophobia among those with migraine. Those with anxiety, more years of headache history, and phonophobia presented significantly more osmophobia. 777

3 Rocha-Filho et al. Table 1 The association of several characteristics with osmophobia among those with migraine: univariate analysis Characteristics With osmophobia (n ¼ 78) Without osmophobia (n ¼ 69) P Odds ratio (95% CI) Age (years): Mean (6SD) ( ) Sex: n (%) Male 5 (6.4%) 8 (11.6%) 0.42 Reference value Female 73 (93.6%) 61 (88.4%) 1.9 ( ) Schooling (years): Mean (6SD) ( ) Anxiety: n (%) 38 (48.7%) 22 (31.9%) ( ) Depression: n (%) 22 (28.2%) 11 (15.9%) ( ) Sought medical assistance for headache 12 (15.4%) 12 (17.4%) ( ) Seeking emergency services because of the 17 (21.8%) 10 (14.5%) ( ) headache in the last 30 days: n (%) Headache attacks duration (hours): Mean (6SD) ( ) Photophobia: n (%) 67 (85.98%) 60 (87.0%) ( ) Phonophobia: n (%) 62 (79.5%) 42 (60.9%) ( ) Headache frequency (days/3 months): Mean (6SD) ( ) Headache intensity (0 10 points): Mean (6SD) ( ) Aggravation by physical activity: n (%) 69 (54.8%) 57 (82.6%) ( ) Pulsating quality: n (%) 61 (88.5%) 52 (75.4%) ( ) Unilateral location: n (%) 50 (54.1%) 47 (68.1%) ( ) Nausea: n (%) 68 (87.2%) 53 (76.8%) ( ) Vomiting: n (%) 46 (59.0%) 33 (47.8%) ( ) Length of headache history (years): Mean (6SD) ( ) HIT: Mean (6SD) ( ) Aura: n (%) 48 (61.5%) 28 (40.6%) ( ) Table 2 Multivariate logistic regression model factors associated with osmophobia among those with migraine Characteristics Osmophobia OR (95% CI) Length of headache 1.03 ( ) 0.03 history(years) Phonophobia No 1.0 Reference value Yes 2.81 ( ) <0.01 Anxiety No 1.0 Reference value Yes 2.21 ( ) 0.03 R 2 ¼ Independent variables considered to the model: age, anxiety, depression, headache attacks duration (hours), phonophobia, nausea, vomiting, length of headache history (years), HIT, aura P Discussion Among our migraine patients, those who had anxiety, more years of headache history, and phonophobia presented significantly more osmophobia. This association between phonophobia and osmophobia has also been found in other studies [2,13]. This is in accordance with the concept that migraine is a disorder of brain excitability and sensory dysmodulation [23]. There was no association between nausea or vomiting and osmophobia. This finding highlights that migraineassociated osmophobia is a specific aspect of migraine and that it is independent of nausea. De Carlo et al. also found an association between osmophobia and the length of headache history among children and adolescents with any kind of headaches. In that study, no evaluation was made regarding the association between osmophobia and the length of headache history among those with migraine [13]. We found the same result among adults with any kind of headaches [9]. 778

4 Migraine, Osmophobia, and Anxiety Only two studies have evaluated the relationship between anxiety symptoms and the presence of osmophobia. In the first one, it was observed that the greater the score on the HADS, the greater the chance of having osmophobia. Osmophobia was the only characteristic of migraine that had a significant association with the HADS score. This study only used the total HADS score, and no assessment can be made as to whether this association was due to the depression symptoms or to the anxiety symptoms [2]. Anxiety and depression symptoms often coexist in patients with migraine, and might affect migraine clinical presentation [24]. The second study used the seven-item general anxiety disorder scale (GAD-7) to assess anxiety symptoms and found that the greater the score on the GAD-7 scale, the greater the chance of having osmophobia [15]. To the best of our knowledge, our study was the first to evaluate the association between the presence of osmophobia in migraine patients and anxiety in a primary headache unit. The processing of olfaction in the brain involves structures of the limbic system. Olfactory tests conducted among individuals with migraine have demonstrated that odors cause significantly greater activation of limbic structures during migraine crises than during the period between crises [25]. Phylogenetically, the medial amygdala evolved from the olfactory system and extended its capacity to detect threats to other types of senses. Its activation recruits cerebral centers involved with anxiety symptoms. Dysfunction of the amygdala is of great importance in the physiopathology of affective disorders [26]. Our study raises the issue of whether the alterations to olfactory processing that occur during migraine crises are more important in anxious individuals. This hypothesis needs to be confirmed through other studies. We did not find any association between gender and osmophobia. This association has been found in some [2,4], but not all other studies [12,13]. We included patients with migraine who were attended within primary care for a variety of reasons and not just because of migraine. This may have brought the characteristics of these headaches closer to those that occur in the general population. Nevertheless, our sample is not representative of the general population. Ninety-one percent of our patients were women and we had higher prevalence of migraine than would be expected for the general population. Our study has some limitations. Because it was a cross-sectional study, we were unable to document the temporal relationship between headache attacks and osmophobia and it is not possible to affirm that there is any causal relationship between anxiety, more years of headache history, and phonophobia and the occurrence of osmophobia. Not using a diary may have led to underestimation of the occurrences of osmophobia, such that the patients may only have remembered this if it occurred more intensely and more frequently. We used a convenience sample, and this may have led to a selection bias. However, this was the same method used by other studies on headaches and osmophobia and therefore allowed comparison with these studies. In conclusion, osmophobia among the migraine patients was associated with anxiety, longer headache history, and phonophobia. Our study was the first to find the interesting association between osmophobia and anxiety in a primary headache unit, but this association needs to be confirmed by other studies. References 1 Silva-Néto R, Peres M, Valença M. Odorant substances that trigger headaches in migraine patients. Cephalalgia 2014;34(1): Wang Y-F, Fuh J-L, Chen S-P, Wu J-C, Wang S-J. Clinical correlates and diagnostic utility of osmophobia in migraine. Cephalalgia 2012;32(16): Kelman L. 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