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Abstract

Objectives

To evaluate the prevalence and the association of psychological disturbance in migraine patients with allodynia.

Methods

We recruited 434 migraine patients from an outpatient clinic. The participants completed three self-administered questionnaires, including a headache questionnaire, an allodynia symptoms checklist, and the Hospital Anxiety and Depression Scale (HADS).

Results

Among the migraineurs, 48.4% participants reported allodynia. The HADS total score (15.5 ± 7.8 vs. 13.7 ± 8.5, p = 0.022) and anxiety subscore (9.1 ± 4.5 vs. 7.6 ± 4.7, p = 0.001) were higher in migraineurs with allodynia than in those without allodynia. The anxiety subscore in patients with moderate to severe allodynia, mild allodynia, and no allodynia were 10.0 ± 4.5, 8.4 ± 4.3, and 7.6 ± 4.7 (p < 0.001, by one-way analysis of variance). Among patients with moderate to severe allodynia, there was a trend of higher depression subscore (7.1 ± 4.0, p = 0.059) than those with no (6.1 ± 4.4) or mild allodynia (5.8 ± 4.0). In a regression model, the presence of allodynia is an independent risk factor for clinically significant anxiety. Moderate to severe allodynia is an independent risk factor for clinically significant depression.

Conclusions

In migraineurs, the severity of cutaneous allodynia was associated with their mood status, especially anxiety.

Keywords

Depression anxiety allodynia migraine

Introduction

Cutaneous allodynia (CA) is a pain sensation in response to non-nociceptive stimulation. The frequency of CA is higher in the migraine population than in patients with other type of headaches (1). Among migraineurs, the prevalence of CA is approximately 60% to 75.3% (1 –4).

Burstein and colleagues proposed an underlying mechanism of allodynia development in a temporal pattern during migraine attack (5). According to this proposal, initial intracranial hypersensitivity during a migraine attack might be due to sensitization of the trigeminal ganglion. Subsequent CA within the referred area might be due to the sensitization of trigeminal neurons in the brainstem, and the extracephalic allodynia that follows might be explained by sensitization of thalamic third-order neurons. Thus, both peripheral and central sensitizations are responsible for the development of allodynia. Since this mechanism was proposed, several studies have confirmed the role of neuronal sensitization in the brainstem and thalamus (5 –8) in the formation of CA.

The presence of CA is a putative risk factor for migraine transformation, the process by which episodic migraine (EM) becomes chronic migraine (CM) (9). Reciprocally, CA influences the regression from CM to EM (6). CA in migraineurs is also associated with multiple comorbid pain conditions, such as irritable bowel syndrome, fibromyalgia, and chronic fatigue syndrome (4). Allodynic migraineurs tend to have more severe headache-related disabilities (10,11) and poor sleep quality (3). Some studies also suggested that treatment with triptans fails when CA has developed during a migraine attack (7,8).

Many risk factors of CA have been reported, including female sex, being African American, having low educational level, high headache frequency, high headache intensity, and a high level of disability. Meanwhile, depression and obesity are two important independent risk factors (1). Psychiatric disorders, such as depression and anxiety, are often comorbid with migraine. The odds ratio (OR) of developing migraine is significantly higher in patients with depression than in those without depression. Reciprocally, migraineurs also have a higher OR of developing depression (12). A prior study demonstrated that migraineurs have a higher OR of having depression, generalized anxiety disorder and panic attacks (13). The relationship between anxiety and migraine was even stronger than that between depression and migraine.

Central sensitization, which might be responsible for the formation of CA, can be modulated by supraspinal processes involving cognition, attention and emotion via descending pathways (14,15). Some studies have demonstrated that pain perception can be modulated by cognition and emotion, such as depression (14 –17). Therefore, the presence of allodynia might be associated with depression and anxiety status in migraineurs. Nevertheless, few studies have examined the relationship between mood and allodynia in migraineurs, and this association remains unclear.

The aim of the present study was to explore the relationships between anxiety and depression and allodynia in migraine patients. We hypothesized that migraine patients with allodynia have a higher risk of having depression and anxiety.

Methods

Patients visiting the headache clinic at Taipei Veterans General Hospital (Taipei-VGH) were invited to participate in the study. Patients were diagnosed according to the criteria of the International Classification of Headache Disorders, second edition (ICHD-2), 2004 (18). Only patients with migraine with aura (code 1.2) or without aura (1.1) were included. In addition, they were classified into EM and CM groups (≥15 headache days/month for ≥ 3 months, with ≥ 8 days of migraine attacks per month) (19). We excluded patients with probable migraine and patients who had any difficulty in communication. The study protocol was approved by the Institutional Review Board at Taipei-VGH. Patients signed informed consent before entering the study.

Study assessment

We recorded demographic data and headache profiles, such as headache intensity, frequency, locations, characteristics, analgesics use and accompanying symptoms, on a headache intake form. The headache intensity was recorded on a 0–10 verbal numeric scale (VNS). Headache frequency was recorded by the average number of days the subject experienced headache every week. Body mass index (BMI) was calculated as body weight divided by body height squared (kg/m²).

CA symptoms checklist

The checklist was designed to identify the symptoms of CA, which comprised the following 17 daily activities: combing the hair, pulling the hair back, shaving the face, wearing glasses, wearing earrings, wearing contact lens, wearing a necklace, wearing anything on the head or neck, wearing anything on the wrist or arm, wearing a ring, wearing a watch, wearing tight clothing, covering the body with a thick duvet, washing the face, resting the face on a pillow, cooking and exposure to cold. The patients were asked to report whether they feel discomfort during these activities or if they avoid these activities during a migraine attack. The patients answered “yes,” “no,” or “I don’t know or it does not apply to me” to these questions. If the answer was “no” or “I don’t know or it does not apply to me,” the symptom would be scored 0. If the answer was “yes,” the symptom would be scored 1. The total score ranged from 0 to 17. According to the allodynia symptoms score, the severity of allodynia was classified as no allodynia (0–2), mild allodynia (3–5) and moderate to severe allodynia (≥6) (11).

Hospital and Anxiety Depression Scale (HADS)

HADS is a self-administered instrument that was developed to detect psychiatric comorbidity in the setting of a hospital medical outpatient clinic (20,21). By avoiding the somatic domain of anxiety and depression, HADS excludes confounding factors of physical signs and symptoms and focuses on specific affective symptoms. It has high sensitivity and specificity for detecting psychiatric disorders in patients with medical illnesses. The scale contains 14 questions, seven for anxiety (HADS-A) and seven for depression (HADS-D). The score of each scale ranges from 0 to 42. The higher the score is, the more severe the symptom. In this study, we used a cut-off point of 7 for the anxiety subscore and 4 for the depression subscore for clinically significant cases (22).

Data analysis

IBM SPSS Statistics, version 18.0, was used for the statistical analysis. Descriptive statistics were presented as means ± standard deviation or percentages. For categorical data, the chi-square test or Fisher’s exact tests were used to test the difference between groups. The Student’s t test and one-way analysis of variance (ANOVA) with the post-hoc least significant difference (LSD) test were used to compare the means of continuous variables. The logistic regression model was used to investigate the relationship between clinically significant depression and anxiety and the severity of allodynia after controlling for confounding factors. Its results were shown as an OR with a 95% confidence interval (CI). All calculated p values were two tailed, and statistical significance was defined as a p value of less than 0.05.

Results

Characteristics of the study population

A total of 434 migraineurs (349 females/85 males, mean age 40.7 ± 13.4 years) participated in this study. The demographics and headache characteristics of these participants are shown in Table 1.

Table 1.

Comparisons of demographics, headache features, and HADS scores of migraine patients with and without allodynia.

All participants	Allodynic migraineurs	Nonallodynic migraineurs	p value
(n = 434)	(n = 210)	(n = 224)	p value
Age (years)	40.7 ± 13.4	38.9 ± 12.4	42.5 ± 14.1	0.006
Sex (females %)	349 (80.4%)	181 (86.2%)	168 (75.0%)	0.003
Education (years)	12.4 ± 4.1	13.0 ± 3.6	11.9 ± 4.5	0.003
BMI (kg/m²)	22.5 ± 3.6	21.97 ± 3.5	23.0 ± 3.7	0.003
Duration of headache (years)	17.7 ± 11.5	18.0 ± 11.6	17.3 ± 11.4	0.522
Intensity of headache (VNS)	6.4 ± 2.0	6.4 ± 1.9	6.4 ± 2.1	0.825
Headache frequency (days/week)	4.0 ± 2.4	4.0 ± 2.5	4.1 ± 2.4	0.649
HADS total	14.6 ± 8.2	15.5 ± 7.8	13.7 ± 8.5	0.022
Anxiety subscore	8.4 ± 4.7	9.1 ± 4.5	7.6 ± 4.7	0.001
Depression subscore	6.3 ± 4.3	6.4 ± 4.0	6.1 ± 4.4	0.426
Anxiety subscore ≥ 7 (%) (clinically significant anxiety)	278 (64.1%)	154 (73.3%)	124 (55.4%)	<0.001
Depression subscore ≥4 (%) (clinically significant depression)	305 (70.3%)	150 (67.0%)	155 (73.8%)	0.119

HADS: Hospital Anxiety and Depression Scale; BMI: body mass index; VNS: verbal numeric scale.

Allodynia symptoms

By defining allodynia as having three or more allodynic symptoms, 48.4% of participants were allodynic migraineurs. The average number of allodynic symptoms among all migraineurs was 4.3 ± 3.1. The most common three allodynic symptoms were avoiding wearing tight clothes, wearing glasses and cooking, and the three least common symptoms were avoiding shaving the face, wearing a ring and wearing earrings (Table 2). Among allodynic migraineurs (n = 210), 53.8% (n = 113) had mild allodynia and 46.2% (n = 97) had moderate to severe allodynia during migraine attacks.

Compared to patients without allodynia, the allodynic migraineurs had a younger age, lower BMI, higher number of years of education, higher total HADS score and a higher anxiety subscore (Table 1). The percentage of females was greater among allodynic migraineurs than nonallodynic migraineurs. The depression subscore, headache frequency, headache intensity and the duration of headache between allodynic and nonallodynic migraineurs did not differ.

Table 2.

The frequency of each allodynic symptom among migraineurs.

“No”	“Yes”	“I don’t know” “It does not apply to me”
Wearing tight clothing	209 (56.2%)	163 (43.8%)	62 (14.3%)
Cooking	196 (45.2%)	152 (35.0%)	86 (19.8%)
Wearing glasses	181 (41.7%)	152 (35.0%)	101 (23.3%)
Pulling the hair back	223 (51.4%)	137 (31.6%)	74 (17.1%)
Resting face on a pillow	265 (61.1%)	105 (24.2%)	64 (14.7%)
Wearing anything on the head or neck	241 (55.5%)	103 (23.7%)	90 (20.7%)
Combing hair	302 (69.6%)	80 (18.4%)	52 (12%)
Wearing contact lenses	138 (31.8%)	78 (18.0%)	218 (50.2%)
Washing face	297 (68.4%)	69 (15.9%)	68 (15.7%)
Covering body with thick duvet	311 (71.7%)	65 (15.0%)	58 (13.4%)
Exposure to cold	284 (65.4%)	57 (13.1%)	93 (21.4%)
Wearing a necklace	251 (57.8%)	52 (12.0%)	131 (30.2%)
Wearing a watch	314 (72.4%)	47 (10.8%)	73 (16.8%)
Wearing anything on the wrist or arm	308 (71.0%)	45 (10.4%)	81 (18.7%)
Wearing earrings	217 (50.0%)	41 (9.4%)	176 (40.6%)
Wearing a ring	309 (71.2%)	34 (7.8%)	91 (21.0%)
Shaving the face	106 (24.4%)	9 (2.1%)	319 (73.5%)

Anxiety and depression subscores and allodynia

The demographics, headache characteristics and HADS total score in the different allodynic severity groups are shown in Table 3. The mean anxiety subscore and the HADS total score were different among different allodynic severity groups (one-way ANOVA, p < 0.001 for anxiety subscore and p = 0.02 for HADS total score). The mean depression subscore did not differ (Table 3). The post hoc LSD tests showed that migraine patients with moderate to severe allodynia had significantly higher depression subscores than migraineurs with no or mild allodynia.

Table 3.

Comparisons of demographics, headache features, and HADS scores of migraine patients with allodynia of different severities.

Severity of allodynia
No	Mild	Moderate to severe
(n = 224)	(n = 113)	(n = 97)	p value
Age (years)	42.5 ± 14.1	39.5 ± 12.9	38.2 ± 11.7	0.017
Sex (females %)	168 (75.0%)	98 (86.7%)	83 (85.6%)	0.013
Education (years)	11.8 ± 4.5^c	12.7 ± 3.9	13.4 ± 3.1^a	0.006
BMI (kg/m²)	23.0 ± 3.7^b	21.6 ± 3.2^a	22.4 ± 3.7	0.005
Duration of headache (years)	17.3 ± 11.4	17.7 ± 12.4	18.4 ± 10.6	0.731
Intensity of headache (VNS)	6.4 ± 2.1	6.3 ± 2.0	6.5 ± 1.7	0.716
Headache frequency (days/week)	4.1 ± 2.4	4.0 ± 2.5	3.9 ± 2.4	0.88
HADS total score	13.7 ± 8.5^c	14.2 ± 7.7^c	17.1 ± 7.7^a,b	0.002
Anxiety subscore	7.6 ± 4.7^c	8.4 ± 4.3^c	10.0 ± 4.5^a,b	<0.001
Depression subscore	6.1 ± 4.4	5.8 ± 4.0	7.1 ± 4.0	0.059
Anxiety subscore ≥7 (%) (clinically significant anxiety)	124 (55.4%)	78 (69.0%)	76 (78.4%)	<0.001
Depression subscore ≥4 (%) (clinically significant depression)	150 (67.0%)	77 (68.1%)	78 (80.4%)	0.045

Analysis of variance (ANOVA) followed by least significant difference (LSD) test as a post hoc procedure was applied for the comparison of means, and the chi-square test was applied to compare proportions. ^ap < 0.05 vs. no allodynia, ^bp < 0.05 vs. mild allodynia, ^cp < 0.05 vs. moderate to severe allodynia. HADS: Hospital Anxiety and Depression Scale; BMI: body mass index; VNS: verbal numeric scale.

A logistic regression model with clinically significant anxiety and depression as the dependent variables and allodynia severity (no, mild, moderate to severe), age, sex, education and BMI as the independent variables was performed. The presence of allodynia was an independent risk factor of clinically significant anxiety, with an OR of 1.82 (95% CI = 1.11–2.99, p = 0.017) for mild allodynia and 2.91 (95% CI = 1.66–5.12, p < 0.001) for moderate to severe allodynia after controlling the confounding factors. Only the presence of moderate to severe allodynia was an independent risk factor for clinically significant depression with an OR of 2.14 (95% CI 1.19–3.86, p = 0.015) after controlling for the confounding factors.

Discussion

Our study showed that allodynic migraineurs had a higher frequency of anxiety. As the severity of allodynia increases, the severity of anxiety increases. In addition, moderate to severe allodynia is associated with clinically significant depression in migraine patients.

There have been few studies regarding anxiety and depression in migraine patients with allodynia, and the results have been controversial. The number of the participants; tools for screening allodynia, anxiety and depression; and the results of these studies are summarized in Table 4. The frequencies of anxiety and depression in allodynic migraine patients were 73.3% and 67% in our study. Tietjen et al. (4) observed a lower frequency of anxiety (36%) and a similar frequency of depression (67%). Two previous studies showed that CA is associated with anxiety and depression, whereas one study failed to demonstrate an association (4,23,24). According to our results, allodynia was associated with clinically significant anxiety, and moderate to severe allodynia was associated with clinically significant depression. However, the screening tools for psychiatric disorders and allodynia among these studies were different. The definition of allodynia and the classification of its severity in our study were similar to the Allodynic Symptoms Checklist used by Bigal et al. (1) and d’Agostino et al. (24), which is a validated tool for screening allodynia. For the measurement of depression and anxiety, the Patient Health Questionnaire-9 (PHQ-9) categorizes a greater proportion of patients with moderate and severe depression than HADS-D (25), and the Beck Depression Inventory (BDI) relies on physical symptoms that might also be the symptoms of underlying illnesses, rather than depression itself. The advantage of HADS is that it avoids somatic signs and symptoms and focuses on psychiatric symptoms. Further studies applying unifying tools or meta-analysis may be needed to confirm the relationships among allodynia and psychiatric comorbidities.

Table 4.

Comparison of studies regarding allodynia and psychiatric disorders in migraine patients.

First author (reference)	Number of patients	Allodynic symptoms questionnaire	Definition of allodynia	Frequency of allodynia	Mood evaluation tools	Results
Lovati (23)	63	One screening question first; followed by asking about seven allodynic symptoms	≥ 1 allodynic symptom	60%	SCL90R	No difference of depression and anxiety between patients with or without allodynia
Bigal (1)	16,573	Allodynia Symptom Checklist: 12-item questionnaire	Score ≥3^a	68.3% in TM; 62.2% in EM; 42.6% in PM	PHQ for depression	Depression is an independent risk factor of allodynia
Tietjen (4)	1413	Six allodynic symptoms questionnaire	>1 allodynic symptom	60%	BAI ≥ 8 for anxiety	Prevalence of anxiety: with vs. without allodynia = 67% vs. 41% (p < 0.001)
Tietjen (4)	1413	Six allodynic symptoms questionnaire	>1 allodynic symptom	60%	PHQ-9 ≥ 10 for depression	Prevalence of depression: with vs. without allodynia = 36% vs. 18% (p < 0.001)
d’Agostino (24)	410	Allodynia Symptom Checklist: 12-item questionnaire	Score ≥ 3^a	63%	STAI Y-2	Migraine patients with allodynia had higher STAI Y-2 scores (p = 0.005)
d’Agostino (24)	410	Allodynia Symptom Checklist: 12-item questionnaire	Score ≥ 3^a	63%	BDI	Migraine patients with allodynia have higher value of BDI (p < 0.001)
Current study	434	Cutaneous allodynia symptoms checklist:17-item questionnaire	Score ≥ 3^a	48.4%	HADS-A ≥ 7	Allodynia is associated with clinically significant anxiety
Current study	434		Score ≥ 3^a	48.4%	HADS-D ≥4	Moderate to severe allodynia is associated with clinically significant depression

Classification of the severity of allodynia: No allodynia (score 0–2), mild (score 3–5), moderate to severe (score ≥6). TM: transformed migraine, EM: episodic migraine, PM: probable migraine, SCL90R: Symptom Check List 90-R, PHQ: Patient Health Questionnaire, BAI: Beck Anxiety Inventory, STAI Y-2: State and Trait Anxiety Inventory; BDI: Beck Depression Inventory; HADS-A: Hospital and Anxiety Depression Scale-anxiety subscore; HADS-D: Hospital and Anxiety Depression Scale-depression subscore.

This study provides evidence that allodynia is a risk of having anxiety and depression in migraine patients. Although the underlying mechanism has not been well established, neuroendocrine systems or neurotransmitters might modulate central sensitization, pain perception, as well as psychiatric disorders. For example, the hypothalamo-pituitary-adrenal (HPA) axis might involve pain processing, which is modulated by depression. Blockade of the HPA axis by administration of hydrocortisone or implantation of dexamethasone above the paraventricular nucleus of the thalamus could reduce stress-induced analgesia (26). Pharmacological management of fibromyalgia, another disorder involving central sensitization of the nociceptive system, can improve anxiety and depression (27). Therefore, it is reasonable to propose an underlying common mechanism modulating both central sensitization of the nociceptive system and psychiatric disorders.

Some neurotransmitters might be involved in both psychiatric disorders and the nociceptive system. Repeated administration of reserpine resulted in a sustained decreased pressure threshold for producing tactile allodynia in rats (28). These animals also showed depression-like behavior. Reduction of biogenic amines, such as dopamine, norepinephrine and serotonin, in the spinal cord, thalamus and prefrontal cortex were observed in these animals. In addition, the melatoninergic system might also play a role in the interaction between pain and depression (29). After peripheral nerve injury in Wistar-Kyoto rats, a preclinical animal model of depression, the mechanical allodynia and depression-like behavior worsened. This worsening can be prevented by administrating melatonin into the anterior cingulate cortex. Further studies are needed to verify the role of these pathways and neurotransmitters in both central sensitization and psychiatric disorders.

Compared with previous reports, the frequency of allodynia in migraineurs was lower in our study (48.4%). In another study in Taiwan (30), only 22.0% of migraine patients experienced brushing allodynia during a gauze-brushing test during migraine attacks. Ethnic differences might contribute to the lower frequency of allodynia in the migraine patients in our study.

Our results showed a lower BMI and a higher education level in migraine patients, whereas previous studies showed a higher BMI (1,4) and a lower education level (1). Because this study required patients to recall their allodynic symptoms during the interictal period, patients with a higher education level tend to have a better ability to complete the questionnaire and a better ability to recall their allodynic symptoms during an attack. Although a role of obesity in migraine pathophysiology and central sensitization has been proposed (31), the effect of obesity on migraine differs in different populations. In a Chinese population, although the prevalence of migraine was higher in those with morbidly obesity (BMI > 30), there was no association between obesity and migraine severity, frequency or disability (32). The variable impact of obesity in different populations might explain our results that allodynic migraineurs had a lower BMI.

Because of high prevalence of allodynia in migraineurs, evaluation of the presence and severity of allodynia is crucial. This evaluation can be performed using a simple allodynic symptoms checklist. Development of allodynia is associated with treatment failure with triptans and the risk of having clinically significant anxiety and depression. Once allodynia is confirmed, anxiety and depression evaluations and a tailored treatment plan are important.

The limitation of our study is recall bias because the allodynic symptoms checklist is a self-reported questionnaire that was filled in between migraine attacks. Also, this was a hospital-based study, which may not represent the whole migraine population. In addition, this is a cross-sectional study and the causal relationship between allodynia and depression/anxiety cannot be certain.

Another limitation of this study is the subjectivity of the participants while filling in the allodynic questionnaire. Patients with depression and panic disorder were associated with an increased frequency of pain complaints, such as low back pain (33). The prior study showed depression and anxiety did not correlate with ratings of physical pain, which was measured by a subjectively answered 100 mm visual analogue scale in patients with fibromyalgia (34). Thus far there is no evidence of whether anxious/depression migraine patients are more likely to have positive answers to allodynic or other pain-associated questions. Further studies exploring this issue are needed.

In conclusion, this study revealed an association between allodynia and psychiatric comorbidities in migraineurs. The presence of allodynia is associated with higher risk of having anxiety and depression, and the severity of allodynia correlates with the severity of anxiety as well as the severity of depression.

Clinical implications

The frequency of allodynia in migraine patients was 48.4%.

Allodynia is associated with clinically significant anxiety in migraine patients.

Moderate to severe allodynia in migraine patients is associated with clinically significant depression.

Allodynia should be screened in all migraine patients and the treatment plan should be tailored individually.

Footnotes

Funding

This work was supported by grants from Taipei Veterans General Hospital (V101C-105, VGHUST101-G7-1-2), the Taiwan National Science Council (101-2314-B-075-037-MY2), NSC support for the Centre for Dynamical Biomarkers and Translational Medicine, National Central University, Taiwan (NSC 101-2911-I-008-001) and the Ministry of Education (Aim for the Top University Plan), Taipei, Taiwan.

Conflict of interest

Dr Jong-Ling Fuh is a member of a scientific advisory board of Elli Lilly and Norvatis, and has as well received research support from the Taiwan National Science Council, Taipei-Veterans General Hospital and Elli Lilly. Dr Shuu-Jiun Wang has served on the advisory boards of Pfizer, Allergan, and Elli Lilly Taiwan. He has received speaking honoraria from local companies (Taiwan branches) of Pfizer, Elli Lilly, Boehringer Ingelheim and GSK. He has received research grants from the Taiwan National Science Council, Taipei-Veterans General Hospital and Taiwan Headache Society.

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Psychiatric comorbidities in allodynic migraineurs

Abstract

Objectives

Methods

Results

Conclusions

Keywords

Introduction

Methods

Study assessment

CA symptoms checklist

Hospital and Anxiety Depression Scale (HADS)

Data analysis

Results

Characteristics of the study population

Allodynia symptoms

Anxiety and depression subscores and allodynia

Discussion

Clinical implications

Footnotes

Funding

Conflict of interest

References