Abstract
Epidemiological studies have identified a number of conditions that are comorbid with migraine (1,2). Failure to classify and analyze comorbid diseases can create misleading medical statistics. Comorbidity can alter the clinical course of patients by affecting the time of detection, prognosis, therapeutic selection and post-therapeutic outcomes (3).
Few putative migraine comorbidities have caused so much debate and confusion as the one with obesity, which is curious, considering that plausible mechanisms to justify the association have been better defined than for many of the other well-accepted comorbidities (4,5). It is my personal opinion that the confusion is partially justified by the fact that several relevant and seemingly overlapping questions about this specific association have been proposed, including: (i) Are episodic migraine and obesity comorbid? (ii) Are frequent migraine headaches and obesity comorbid? (iii) If so, is the association specific to migraine, or is the association seen for any headache (or pain)? (iv) Is obesity not only associated with, but a risk factor for, migraine or frequent migraine headaches? (v) Alternatively, are migraine or chronic migraine risk factors for incident obesity?
These are indeed very different research questions, often presented in a confusing framework with misleading conclusions. In the current issue of Cephalalgia, Winter and colleagues analyzed data from the Women’s Health Study (WHS) to examine whether having migraine is a risk factor for becoming overweight or obese (6). Although focusing on one of these questions, this very robust study offers us an opportunity to comment on the others as well.
The study by Winter et al. is unique for many reasons. The WHS enrolled nearly 40,000 women aged 45 years or older at study entry. They were meticulously followed for more than a decade. Furthermore, being a clinical trial designed to test the benefits and risks of low-dose aspirin and vitamin E in the prevention of cardiovascular disease and cancer (7), exposures of interest (e.g. nutrition, exercise, health status) were collected more meticulously than in most other migraine cohorts. The sample size, quality of information and longitudinal nature of the study were matched by very sophisticated and elaborate statistical analyses, with robust adjustments. Three limitations are worth mentioning. First, migraine and body weight were self-reported. Self-report of migraine seems to have good correlation with gold-standard diagnosis as reported by the authors. Self-reported weight is of little concern, because biased information would most likely equally affect those with migraines and those without migraine. Second, the mean age of patients with migraine at the start of the study was 56 years. Third, headache frequency was categorized in less than monthly, monthly, weekly, and daily time periods, and the last two categories were pooled together, therefore lumping participants with 4 to 30 headache days per month in a single category.
The authors analyzed participants (with or without migraine) with normal weight at study entry. After almost 13 years of follow-up, 49.3% became overweight and only 3.8% became obese. Findings were strikingly similar comparing participants with migraine and controls, leading the authors to conclude that migraine is not a risk factor for becoming overweight or obese. The authors also failed to identify an association between frequent headaches and incident overweight or obesity.
What have the authors achieved? To the best of my knowledge, this is the first study to address whether migraine predisposes to obesity. All other studies focused on the other research questions listed above. This is the first study to look at the missing piece in a robust and very strong way. Their answer is a categorical no – neither migraine nor migraine frequency predispose to increased body weight.
What was not achieved by the authors? The baseline age of participants is of concern. After nearly six decades of life, patients were of normal weight. Although we don’t know if they had ever been obese, we know that they were not at study entry. Peak prevalence of obesity happens during the 4th and 5th decades of life (8). Accordingly, it may be that the assessed sample as indeed ‘resistant’ to become obese and non-representative of what happens at younger ages. This is relevant, because the age influence on the migraine obesity comorbidity has been suggested (9). There is nothing the authors could have done in this regard and they properly acknowledge the limitation. Additionally, the lack of influence of headache frequency on body weight needs to be taken cautiously, because the authors were forced to consolidate data from patients with low headache frequency (as little as four headaches per month) with high headache frequency (as much as daily). Future studies need to more precisely focus on the influence of high frequency of headaches on body weight.
Where does the field stand after the portrayed study? It is our impression that we now have evidence to at least partially respond to all the questions listed above. First, are episodic migraine and obesity associated? No, they are not, as the convergent evidence strongly supports. In a large population-based study with a sample of 30,215 participants and robust adjustments, the association was not found (10). Obesity was, however, associated with the frequency of headache attacks. A second large study from the group of Winter et al. literally confirmed our findings by demonstrating that migraine prevalence did not vary significantly as a function of body weight, and that severely obese women were more likely to have increased headache frequency (11). Several other studies presented similar findings.
Second, is obesity a risk factor for migraine chronification (frequent migraine attacks)? Yes, it is. Several population-based, well-adjusted cross-sectional studies confirmed the association (11–14), and longitudinal studies confirmed the directionality of the association (13,15). Furthermore, the magnitude of exposure (obesity) influences the magnitude of the outcome (frequency of headaches) (16), and it seems that Hill’s criteria for causality have been fulfilled (17).
Third, is the association specific to migraine or is it verified for any headache? Limited data addressed this research question suggesting, however, that obesity predisposes to migraine, not to any headache, chronification (12), which is in line with the biological plausibility.
Finally, Winter et al. presented data that do not allow us to suggest that migraine is a risk factor for obesity, and with the cautions listed above, it does not seem to be for frequent headaches as well. In our opinion, this is the second very strong point of their study. Not only did the study address a gap in the current knowledge, but it helps to further understand the directionality of the association. Migraine is not comorbid with obesity. Frequent migraines are comorbid with obesity with clear directionality. Obesity increases the risk of frequent migraine, and the opposite does not seem true. The clinical relevance and take-home message for clinicians therefore becomes obvious. Be careful with the association, as you would be when treating a patient with migraines overusing opioids. These are not empty calories.