Abstract
Aims
Migraine and depression have a strong association. We aimed to determine whether this relationship was particularly evident in migraineurs with allodynia.
Methods
A cross-sectional study was carried out of 98 consecutive patients with episodic migraine presenting for their first evaluation in an outpatient clinic. The participants completed a demographic questionnaire, the Allodynia Symptom Checklist and the Hospital Anxiety and Depression Scale (HADS).
Results
Among the migraineurs, 75 (77%) reported allodynia. Allodynia was associated with higher median HADS-Anxiety (9 vs. 6, p = 0.038) and HADS-Depression (6 vs. 4, p = 0.014) scores. In a multiple regression model, the HADS-Depression scores were independently associated with allodynia (odds ratio 1.236, 95% confidence interval 1.046–1.461). An increased severity of allodynia correlated with higher depression scores (r = 0.224; p = 0.027).
Conclusion
Anxious and depressive symptoms are more common in migraineurs with allodynia than in those without allodynia. Further studies are necessary to clarify the relationship between depressive symptoms and allodynia, as well as its therapeutic implications in migraine.
Keywords
Introduction
Depression and migraine are common disorders with a bidirectional relationship: migraine increases the risk of depression and depression increases the risk of migraine (1).
Allodynia, a painful response to non-painful stimuli, is a common symptom in migraine (2), with an estimated prevalence of around 60% (3). Allodynia has been proposed as the clinical manifestation of the central sensitization occurring in migraine (2). Monoaminergic and serotoninegic pathways seem to be dynamically involved in pain processing and central sensitization (4). It is also believed that these same pathways have a role in depression. Interestingly, clinical data have shown that both allodynia (5) and depression (6) are risk factors for migraine becoming chronic, increasing interest in the possible relationship between these disorders.
The aim of this study was to evaluate the relationship between allodynia and depressive symptoms in migraineurs.
Methods
Participants
From September 2013 to April 2015, all patients with headache referred to a neurology outpatient consultation in a tertiary hospital were evaluated in a local headache outpatient clinic. At the first evaluation, consecutive patients with a diagnosis of migraine according to the International Classification of Headache Disorder (previously ICHD-II, now ICHD-III beta version) (7) criteria were asked to participate in the current study. We excluded patients with a diagnosis of chronic migraine. No exclusion was made on the basis of the presence of overlap headache syndromes (i.e. patients with a simultaneous diagnosis of another headache disorder, such as a medication-overuse headache or a tension-type headache, were included in the study). Patients were included even if they were receiving prophylactic migraine drugs. Oral informed consent was obtained for all participants.
Measures
Demographic and social data were obtained for the participants. Symptoms of anxiety and depression were evaluated using the Hospital Anxiety and Depression Scale (HADS), a 14-item questionnaire, of which seven questions are about anxiety (HADS-A score) and seven about depression (HADS-D score), each with a score ranging from 0 to 21 (8). Cutaneous allodynia was measured using the 12-item Allodynia Symptom Checklist (ASC-12). This is a scale that evaluates the frequency of thermal, mechanical static and mechanical dynamic allodynia in association with headache attacks to give scores ranging from 0 to 24. The presence of allodynia is defined as a score of at least 3. Allodynia was divided in mild (score 3–5), moderate (score 6–8) and severe (score ≥9) allodynia (3).
Data analysis
The groups with and without allodynia were compared using the Mann–Whitney U test for continuous variables and the χ2 or Pearson’s exact tests for categorical variables. Logistic regression analysis was used to test which variables were independently associated with allodynia. All significant variables were introduced in the model and the variables with a lower significance (higher p value) were sequentially removed from the model. The relationship between severity of allodynia and depression was studied with Spearman’s rank correlation coefficient. p < 0.05 was considered to indicate statistical significance. Analysis was performed using IBM SPSS version 20.0 for Windows (IBM, Armonk, NY, USA).
Results
Study population and descriptive statistics
Baseline characteristics of 98 patients with migraine according to the presence or absence of allodynia.
IQR: interquartile range.
χ2 test.
Mann–Whitney U test.
Fisher’s exact test.
Current use or history of use of prophylactic drugs.
Setraline, six patients; fluoxetine, five patients; escitalopram, five patients; venlafaxine, three patients; paroxetine, two patients; duloxetine, one patient; bupropion, one patient.
This data was missing for seven patients as a result of non-response. All the seven patients had allodynia. These seven patients had a significantly higher body mass index (28.3 ± 5.0) than the rest of group with allodynia (24.5 ± 4.6; p = 0.04a). No other difference was found between these seven patients and the rest of the group with allodynia.
Allodynia in patients with migraine
A significant univariate association with allodynia was found for the anxiety (HADS-A) and depression (HADS-D) scores and for the use of antidepressant drugs. No significant difference was noted in the number of migraine episodes. The variables with a univariate association were introduced to a multivariate logistic regression analysis. We did not include the use of antidepressant drugs in our model as this was highly associated with the HADS-D score. This analysis resulted in a univariate model showing that the depressive scores were independently associated with allodynia with an odds ratio of 1.236 (95% confidence 1.046–1.461, p = 0.013).
A correlation was observed between the severity of allodynia and the HADS-D score. A significant (p = 0.027), but weak, correlation (r = 0.224) was found between allodynia and the depression scores (Figure 1).
Median HADS-D score for each category of allodynia. Error bars represent 95% confidence intervals.
Discussion
This cross-sectional study of patients with migraine showed that depression and anxiety are more common in migraineurs with allodynia, but that only depressive symptoms are independently associated with allodynia.
Studies evaluating anxiety and depression in migraineurs with allodynia have recently been summarized (9) and the results are controversial. ASC-12 was used in three studies (3,9,10) addressing depression in migraineurs. ASC-12 is a tool used for cephalic allodynia screening in patients with headache. It was validated using item-response theory, but no study has yet related this tool with objective, quantitative sensory testing measures. One study that evaluated depression using the Patient Health Questionnaire-9 (PHQ-9) found that depression was an independent risk factor for allodynia (3). A second study also found a higher prevalence of depression in migraineurs with allodynia using the Beck Depression Inventory (BDI) (10). For the measurement of depression and anxiety, PHQ-9 categorizes a greater proportion of patients with moderate to severe depression than HADS-D (9,11) and BDI relies on physical symptoms that might also be the symptoms of an underlying illness rather than depression. In a third study (9), an association was found between allodynia and anxiety and depression, but it was only independently associated with anxiety. In this study, the HADS-D and HADS-A scores were treated as binomial variables using cut-off scores of 7 for anxiety and 4 for depression. The utility of a cut-off score for diagnosis in HADS has been questioned (12), and, in most studies, an optimum balance between sensitivity and specificity is achieved when a case is defined as a score of ≥8 for both depression and anxiety (13). The use of a lower cut-off score, leading to a lower diagnostic specificity, could contribute to the absence of an independent association with depression. Our study is the first to evaluate the relationship of allodynia not with the diagnosis of depression, but with the severity of the depressive symptoms. We found that for each point increase in the HADS-D score, the risk of allodynia increased by 24%.
Our study is also the first to show that as the severity of allodynia increases, the intensity of depressive symptoms also increases (Figure 1), suggesting a relationship between allodynia and depression. The underlying mechanisms for this relationship remain to be elucidated, but both neuroendocrine and neurotransmitter systems may have a role in central sensitization (clinically evidenced as allodynia) and depression. Serotonin has a role in processing and modulating migraine pain and chronically low levels of serotonin predispose to prolonged activation and sensitization of the trigeminovascular nociceptive system (4). In animal models of persistent orofacial pain, serotonin seems to have a role in the central sensitization and persistence of pain (14). Simultaneously, a role for serotonin has been hypothesized in depression and the current drugs of choice for the treatment of depression are based on the serotonin system (serotonin-selective or serotonin-norepinephrine reuptake inhibitors). However, the usefullness of serotonin-selective reuptake inhibitors migraine treatment has been shown to be residual. A recent meta-analysis evaluating the effectiveness of different prophylactic drugs for migraine identified six serotonin-selective reuptake inhibitors trials. Only one trial (40 patients, fluoxetine vs. placebo for 12 weeks) found a significant, but modest, reduction in the monthly frequency of migraine (15). Despite residual and conflicting evidence, we speculate whether there is an underlying common mechanism linking central sensitization and depression. As both are risk factors for chronic migraine, a common pathophysiological pathway, or at least some type of interaction, cannot be ruled out.
In migraineurs, a higher frequency of migraine is known to been associated with the development of allodynia (2). It could be hypothesized that this higher frequency of migraine, or a higher total number of days with migraine, could lead to more depressive symptoms. In our cohort of patients with episodic migraine, no significant difference was found in the number of headache episodes between the groups with and without allodynia, precluding this interpretation. Nevertheless, our analysis may not have had sufficient power to find a difference in this parameter as a result of our small sample size.
As limitations of our study, we suggest that the use of a hospital-based sample may not represent a migraine population and a bias towards more severe phenotypes cannot be excluded. The cross-sectional design does not allow the establishment of a causal or temporal relationship between depression and allodynia. In addition, as ASC-12 has only been validated using item-response theory and has not been compared with quantitative sensory testing (the gold standard), care should be taken in interpreting the meaning of these results.
This study has revealed an independent association between depressive symptoms and allodynia, with the severity of depressive symptoms increasing with the severity of allodynia. Future studies exploring the mechanisms behind this association are necessary and could lead to the discovery of new pathways for both depression and migraine research and treatment. To clarify this link, an interesting study would involve modifying the ASC-12 and testing it in patients with depression without headache. This would provide information on the prevalence of allodynia-like symptoms in patients with depression.
Clinical implications
The frequency of allodynia is high in patients with migraine. Depressive symptoms are associated with allodynia. Allodynia is correlated with the severity of depressive symptoms.
Footnotes
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Contribution of authors
MDM and AC participated in study conception, design and data collection. All authors participated in data interpretation and drafting the manuscript. All authors read and approved the final manuscript.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.