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Voice-over: Welcome to Spotlight on Migraine, The Professional Series, hosted by the Association of Migraine Disorders. Join us as we dive deeper into migraine topics with guests from the medical field. This episode includes educational content intended for medical professionals but may be interesting to some patients as well.

In this episode, we see two presentations on migraine and obesity. The first, by Dr. Alison Field, summarizes research findings that suggest a link between obesity and migraine. Dr. Dale Bond then explains potential strategies to treat obesity, which in turn aim to alleviate migraine.

This episode is brought to you in part by our generous sponsors Amgen and Novartis.

Dr. Alison Field: I’m Alison Field, and it’s a pleasure to be speaking with you today, albeit remotely, on obesity and migraine. I’m first going to talk a little bit about the association and how strong is the evidence that there is a relationship between obesity and migraine, and then discuss why that association might exist. What are the possible mechanisms? I’m then going to spend some time talking about sex and age group differences in the strength of the association and conclude with some thoughts about the next steps that we need to take in research to have a much clearer idea of why this association might exist.

So one of the challenges we have in answering “Is obesity associated with migraine?” is that most of the research on migraine has been conducted among adults with migraine, asking the question “What causes more migraine attacks?” Much, much less is known about why do people develop migraine in the first place. Obesity is known to be more common among adults with chronic migraine compared to those with no or infrequent headaches, and just probably more common among people with any frequency of migraine, compared to those without migraine.

So why? Why would they be associated? Well, one thought is it might be through an inflammatory pathway. We know obesity is an inflammatory state. We know that middle-aged women who have migraine with aura are at an increased risk of developing stroke, so one thought could be this might be through an inflammatory pathway. However, the stronger evidence is that the association is really through a hormonal pathway. There’s pretty much consensus that sex hormones are related to migraine, and we know that obesity, at least in women, is very strongly related to sex hormone levels.

Now, the story, it gets much more complicated very quickly because there’s a paper in 2013 by Schramm et al. that found that, in their analysis between migraine and obesity, the association was attenuated and no longer significant once they took into account whether people were taking pain medication. Well, that’s an interesting finding. It leaves you asking, “Do people with migraine gain weight because of migraine-related disability, so it’s the migraine that’s leading to the weight gain? Or is it obesity that leads to greater migraine frequency?” And, unfortunately, with a cross-sectional design, you just can’t disentangle the two and you can’t answer that question.

Most of the studies, most all of them that have looked at the association between obesity and migraine, are cross-sectional. Most of them have found a positive association, but not all of them, and you are left trying to answer the question, “Well, which comes first?” The good news is there has been one large prospective study. This is about 19,000 middle-aged women in the Women’s Health Initiative, and they found that women with migraine were more likely than their peers to develop overweight or obesity, about 11 percent more likely. And this was true whether the women had migraine with aura or without aura. So that’s a very strong finding.

It’s an interesting age range to study, however. So middle-age sort of depends on how you define it. The older I get, the more liberal I am in my definition of middle age. But let’s just say they’re looking at women in their 40s, 50s, and maybe 60s. And you can see that’s when the prevalence of migraine is going down; there are fewer women with migraine. So it’s an interesting age range to study. Most people are developing migraine much earlier in life. So the peak incidence is between the teen years and the 30s.

Obesity also has an interesting pattern with age. Unfortunately, in the US, obesity is very common. By late adolescence, about 20 percent of young people will have obesity. That rate increases through their 20s, 30s, 40s, and 50s, before decreasing over time. So, sometime during middle age, the rates stop increasing and they start decreasing. So studying middle-aged adults is a difficult time frame to study when you want to extrapolate results to all ages.

As with all of these studies that we’ve been thinking about, with a cross-sectional design you don’t know which comes first. And with a prospective design in middle age, which is past the peak period of incidence, the question is “Are risk factors similar earlier?” If you’d studied women who were in their 20s, would you have seen the same association? And we simply don’t know.

There have been some meta-analyses that have been done trying to understand the strength of the association between obesity and migraine, and most of them have found a lot of heterogeneity. So the results vary from study to study. If you put them all together and you try to get a summary estimate, in the Ornello et al. meta-analysis in 2015, they found a suggestion of an increase in risk, almost a 20 percent increase in risk, but the association was not statistically significant.

A more recent meta-analysis by many of the same authors with more studies still found a lot of heterogeneity, so a lot of differences between the studies, some finding increase in risk, some finding a protective effect. But, overall, there was a statistically significant association of a small increase in risk. But the heterogeneity was really large. So, in some studies, you could see as BMI increased, so did risk. It went right up. In other studies, it was quite flat. So the results vary study to study, as do the age ranges of these studies, how they’ve assessed migraine — a lot of heterogeneity.

What seems to be more consistent in most studies — not all, but most studies find the increase in risk is much stronger in women. So here’s an example from the 2015 Ornello et al. meta-analysis, finding about a 40 percent increase in risk for women to have migraine if they had obesity.

Now, I should say this is what’s seen in most studies, but a very recent paper from the HUNT study, which is a large cohort in Norway, actually found an increased risk in men that was higher than in women. Puzzling result — I’m sure we’ll be talking about it a lot in the future — but it is a cross-sectional study. Results may vary country to country, and that’s important to keep in mind.

Most of the studies find that the association is strongest during the reproductive age, in younger ages, particularly in women. So reproductive age is a little longer in men than in women, but migraine is more common in women, and the associations are strongest at youngest ages.

So here, once again, from the HUNT 3 cohort, they find that the cross-sectional association between migraine and headache is strongest among those who are less than 50 as opposed to more than 50. In the group who’s more than 50, there was no association. Those who are overweight or obese were no more likely than their leaner peers to have migraine, whereas the association got stronger the heavier the group was. So overweight women, about 24 percent increase in risk of having migraine, and that risk was even stronger with obesity.

Now, the fact that the association gets stronger with more extreme excessive weight adds some credence to the finding and makes you feel that that’s probably a real finding. That’s the direction you should expect: the more severe the obesity, the stronger the association.

A very, very nice study by Peterlin also demonstrates this quite beautifully. So body mass index is what we very often use to measure obesity, and that’s a measure of weight over height — strongly related, very strong correlation, with actual measured body fatness.

Now, the one limitation, or one of the limitations, of BMI is that it can’t differentiate lean mass from fat mass. Now, in the US, and unfortunately much of western Europe, we’re not very active, so this is not a big problem. It classifies people quite well. But when people are very active and they have a lot of lean mass, muscle is heavy. So you could be very active and have a high BMI but a low body fat. In that case, BMI could misclassify you. So if we ever become a very active population, BMI will be terrible, but until then, it works quite well.

One of the nice things about this paper is that they looked not only at obesity defined by BMI, but they also looked at it in terms of waist circumference. We know that carrying your weight centrally, so in larger waist circumference, higher risk for many adverse cardiovascular outcomes, much more strongly tied to body fatness. What they found — and they found this in men, who are in yellow, as well as women, who I’ve highlighted in blue — the same pattern.

So among younger people, those who had higher BMI or had a higher abdominal obesity were at increase risk with having a migraine. That pattern was seen in women, and you can see the migraine rates are going way down as they get in their 60s, 70s, and 80s, regardless of how — and the association goes away — regardless of how you’re using metrics to define obesity. So really clear example of the association going away as people become older. Sort of put it all together, and you can find overall there’s an association, but that’s driven by younger individuals.

So why does it go away? Well, there are quite a few reasons for this. First, over time, we have a change in body fat distribution. We very often see that as people age and become elderly, they will start carrying more of their weight centrally. Now, the complicated thing is that their body mass index may stay exactly the same. They haven’t gained weight, haven’t lost weight, but where they’re carrying it has changed. And that makes a big difference because carrying it centrally tends to be higher risk.

We also know in women there are very large changes in hormonal profile. So sex hormone levels are much higher among women in their 20s, 30s, 40s, and they change quite a bit as they head into perimenopause, where they can fluctuate greatly, and then very low postmenopause unless they’re taking hormone replacement therapy.

We also know there’s a change in the prevalence of migraine, and that matters because if something is less common, it can be harder to find an association. And the validity of BMI, which is how most studies measure obesity, is less in the elderly. In fact, we don’t recommend using it in the elderly because of the reason I stated in the beginning about this change in body fat distribution and that people’s BMI could stay the same, but their risk of adverse events could increase. You put it all together, and it makes a lot of sense why the association is much stronger in younger individuals.

And as I mentioned, the change in prevalence — so, in the elderly, you’re seeing low rates. That’s important because up here, if you have 20 percent of people who unfortunately — or, 20 percent of women suffering from migraine, if you have a fairly large study, you have lots of cases. It’s easier to pick up an association between two factors. When migraine becomes less common, you need an even larger sample to find an association, and if that association is getting smaller over time, you’re probably going to miss it unless you have an enormous study.

So why do we see the sex differences? Well, sex hormones clearly are a very large reason for it, but there are two other factors to keep in mind. One is migraine incidence spikes up around puberty in females. So rates are low and pretty similar in males and females until puberty, and then the rates really go up in females but not in males. That’s the time that females are going to be putting down more fat mass and males more lean mass, so their body composition can be quite different. And where they carry fat is very different in men and women, which may also add one more reason why we see these large sex differences.

So where do we go from here? Well, there’s a lot more research we need to do. We need to figure out which comes first, obesity or migraine. Does obesity promote the development of migraine? Well, to answer that, we can look at several different study designs. We could look at weight-loss trials and see when women lose weight, do they have migraines less frequently. That would suggest — not perfectly — but it would suggest that obesity is the driver of the migraine association.

How about looking at younger ages? While we think that the risk of developing migraine is the highest, how about all the obesity-prevention interventions that are going on? Could we look at the successful ones and see among high-risk individuals — so individuals who have migraine in the family, genetically at risk — in these interventions that are successful, are they less likely to develop migraine?

Once we’ve answered those questions, we can answer the next questions, which are “Is this true for migraine with and without aura? Is this true for males and females, if our sample sizes are big enough, and is the association between migraine and obesity true and similar across the age range?” And these are all really important questions to answer scientifically and to answer to help patients.

Dr. Dale Bond: Hello. The title of my talk is “Treating Obesity to Treat Migraine: Worth the Weight?” And during my talk, I’m going to address five questions. The first is, Does treating obesity improve migraine? Does the method of obesity treatment matter? Is weight loss the primary treatment mechanism? Does migraine influence one’s ability to lose weight? And should headache physicians advise their patients who have migraine and comorbid overweight or obesity to lose weight?

Two formal obesity treatment methods have been studied in the context of migraine management, and these methods are bariatric surgery and lifestyle modification. So I’m now going to first delve into the question of whether migraine headaches are improved after bariatric surgery.

Bariatric surgery is now regarded as a first-line treatment for severe obesity and its comorbidities, and given its profound impact on type 2 diabetes and other comorbidities, there’s increasing calls for it to be available as a treatment to individuals who have mild obesity and comorbidities. Approximately 240,000 procedures are performed each year in the US, and the most commonly performed procedure is the vertical-sleeve gastrectomy, followed by the Roux-en-Y gastric bypass. And both of these procedures involve changes in the gut anatomy that yield hormonal and neural changes that impact on energy balance, metabolism, hunger and appetite, and disease processes to produce weight loss and improvement in comorbidities.

And a point that I’m going to continue to emphasize throughout this talk is that bariatric surgery produces vastly superior weight loss and health improvements as compared to nonsurgical weight-loss methods such as lifestyle modification. And to give you an example of that, to the right you’ll see illustrations of three different procedures and a weight-loss trajectory for each. And this figure is from a recent PCORI study that looked at data from over 65,000 patients from 41 different health systems who had one of these three procedures between 2005 and 2015.

So let’s start at the bottom, and, as you can see, the Roux-en-Y patients lost the most weight. They lost about 33 percent of their initial body weight between 12 and 18 months postsurgery. The sleeve-gastrectomy patients are in the middle. They lost about 23 percent of their initial body weight. And patients who had adjustable gastric banding, the ones at the top, they lost about 13 percent of their initial body weight. The gastric banding is the least invasive procedure, but it’s also the least performed procedure now of the three in the United States. And across the three methods, you’ll see that weight regain occurs after bariatric surgery, like any other weight-loss method.

I’d like to now present data from a study we conducted nearly a decade ago, and this study was the first to evaluate changes in migraine headache frequency, pain intensity, and disability after bariatric surgery. And, in this study, we used the ID-Migraine screener to identify patients, and slightly over 20 percent of 274 patients screened positive preoperatively. And of these patients, we studied 24 who both had surgery and also provided postoperative data. And we used the MIDAS to assess headache outcomes at pre- and six months postoperatively.

And, as you can see in this table, the participants on average were about 39 years of age, they were mostly female, and most had white, non-Hispanic race and ethnicity. And, in this study, participants either had the Roux-en-Y gastric bypass or the gastric-banding procedures. And, on average, the bypass participants lost about 40 kilograms at six months postoperative, whereas the gastric-banding patients lost about half of that, or about 24 kilograms at six months postoperative. And, on average, participants reported a reduction of 1.5 headache days per month, as well as significant reductions in pain intensity and related disability.

This figure shows weight loss overall and for each type of bariatric procedure by changes in headache days, so it provides more detail on variability and headache response, as well as the relationship with amount of weight loss. And, overall, you’ll see that responders, or those patients who reported a reduction in headache days, also had greater weight loss. On average, they lost about 10 kilograms more than nonresponders, or those participants who reported no change or an increase in headache days. And, interestingly, this relationship was significant regardless of surgical procedure; thus, independent of whether participants had either Roux-en-Y gastric bypass or adjustable-gastric banding, greater amount of weight loss was associated with a reduction in headache days.

Since our initial study, a few other studies have been conducted, and overall findings from these latter studies support our initial findings. However, as reported in a recent meta-analysis, effects for both headache frequency and pain intensity are larger in the latter studies compared to our study. And while the reasons for this are not entirely clear, it might be due to differences in samples. For example, the latter studies had more premenopausal women, and the relationship between obesity and migraine is strongest in this particular subpopulation. These other studies also used different headache-assessment tools. And note the effects for both headache frequency and pain intensity after bariatric surgery; as you can see, the effect for pain intensity is larger than that for headache frequency.

It’s also important to note several limitations across studies of changes in migraine headaches after bariatric surgery, and these include small sample sizes. Also, none of these studies have involved randomization, and there’s also large variability in method and the quality of headache reporting. And also bariatric surgery may not be a practical treatment option for many patients with migraine.

OK, so now I’d like to shift treatment methods and examine whether migraine headaches improve after lifestyle-modification approaches. Before I get into the data, however, I’d like to provide a brief overview of what these approaches, also referred to as behavioral weight-loss treatments, involve. And these interventions involve teaching cognitive-behavioral strategies — for example, self-monitoring, goal setting, and problem solving — to promote consumption of a reduced-calorie diet and to increase physical activity. They typically involve at least 14 individual or group counseling sessions over a period of six months, and the goal is to help these individuals lose an average of 5 to 8 percent of their initial body weight, and this translates to roughly a 10-to-16-pound weight loss.

And, as you can see in this figure, individuals achieved maximum weight loss at about one year, after which point there’s considerable variability in the amount of weight loss that’s maintained, although the majority of these participants regain half or more of the weight that they lost after reaching their maximum weight loss. These lifestyle-modification approaches are also increasingly delivered in the community, for example, in YMCAs, as well as digital platforms such as Weight Watchers.

Our team conducted the first randomized controlled trial of a lifestyle-modification approach to treating comorbid obesity and migraine. This trial was called the Women’s Health and Migraine trial, or the WHAM trial, and it compared the effects of a standard behavioral weight-loss intervention and migraine-education active-control condition on migraine headache frequency and severity in women who were aged 18 to 50 years.

This figure depicts the WHAM study design. And so after initial screening, participants completed a four-week smartphone-based headache diary before being randomized to 16 weeks of either behavioral weight loss or migraine-education control. Both interventions were group based and conducted at our research center, and in the behavioral weight-loss intervention, there was no discussion of or strategies offered on migraine management. And in the migraine-education condition, there was no discussion of or strategies offered on obesity or weight control. Participants then completed the smartphone headache diary for four weeks at the end of treatment and then four months later at follow-up.

This table shows characteristics of the 110 participants who were randomized to the behavioral weight-loss and migraine-education control conditions, and, on average, participants were 39 years of age. About 22 percent of participants had non-white race. Nearly 60 precent had at least a four-year college degree, and 57 percent were married. On average, participants had severe obesity. They experience five headache attacks and eight headache days per month, and slightly less than one-quarter used preventive medications.

So this figure shows differences in weight change between the two groups. And the behavioral weight-loss group, represented by the black bars, on average achieved about a 4 kilogram weight loss at post-treatment or 16 weeks, whereas the migraine-education group, represented by the gray bars, gained about 1 kilogram at post-treatment, so about a 5 kilogram differential between these two groups. And this difference was largely maintained at follow-up.

Here we now see differences in migraine headache days between the groups. And the behavioral weight-loss group reported an average reduction of about 3 headache days, whereas the migraine-education group reported an average reduction of about 3.8 headache days at post-treatment. However, the groups did not significantly differ on this outcome at either post-treatment or follow-up.

And the pattern that we found for other headache outcomes between the groups was similar as what we found for headache frequency. And so we found similar reductions in pain intensity, average headache duration, as well as headache impact, with both groups again reporting significant but similar reductions from baseline at both the end of treatment and follow-up.

So I’d now like to summarize and discuss the main finding from the WHAM trial. And so, contrary to our primary hypothesis, both groups on average had significant improvements in headache outcomes at the end of treatment that were then maintained at follow-up. However, we found no differences between the groups at either time point. And so an obvious question is “Why?” and especially given the 5 kilogram weight difference between the groups at post-treatment.

And so one possibility is that the amount of weight loss was insufficient; however, I want to note here that the amount of weight loss achieved by participants with lifestyle modification was one-tenth of that which occurred after gastric-bypass patients in their earlier study I showed you. But, interestingly, the magnitude of change in migraine headache days after lifestyle intervention in the WHAM trial was double compared to that after bariatric surgery.

It’s also possible that migraine might interfere with ability to lose weight or adhere to behavioral prescriptions that are part of lifestyle-modification interventions. For example, research in nonmigraine populations shows that higher pain intensity is related to poorer weight loss after lifestyle intervention. Also, both human and animal research suggests that high-calorie, palatable foods might soothe pain. This could then interfere with dietary prescriptions. Also, research from our group suggests that migraine attacks could reduce available time to engage in physical activity, and, in some cases, individuals with migraine may actually avoid exercise because they believe it will trigger or worsen their attacks.

It’s also possible that our control group, which provided 16 hours of migraine education over 16 weeks in a group-based format with other women suffering from migraine, may have been too powerful. This control condition was really effective in not producing weight loss, and it also enabled us to rule out confounding effects of treatment contact and format, but it was also much more intensive than what would be provided in the context of standard care.

I’d like to now return to the question of whether obesity treatment method matters. And so, up until this point, I’ve shown you that, on average, improvements in migraine headache frequency and severity are observed after both bariatric surgery and lifestyle-modification approaches. And given that there’s such a large difference in the amount of weight loss that’s produced by these different treatment methods, it really begs the question of whether weight loss is the principal mechanism.

Also, it’s important to note that after bariatric surgery, headache improvements are not always related to weight loss, and in one study, headache improvements persisted after controlling for weight loss. We also saw in the WHAM trial that the conditions had similar improvements despite the behavioral weight-loss intervention group losing more weight and the migraine-education group gaining weight. So, if weight loss is the principal mechanism, wouldn’t more weight loss yield more benefit?

This question was addressed in the recent meta-analysis that I showed you earlier. And so, if we look and we compare the overall effects across bariatric-surgery and behavioral-intervention studies, we see that the magnitude of effect for headache frequency in this case is very similar between treatment methods despite large differences in weight loss. We also see similar findings for pain intensity, although the overall effect is larger for pain intensity for both treatment methods and the difference is slightly larger between methods.

So, given all that I have presented thus far, I want to return to the original question of whether treating obesity improves migraine. So, overall, the evidence to date would indicate that the answer to this question is yes, but, of course, there’s some important caveats. And so, as I had mentioned previously, the answer to this question might be yes, but it appears to be so regardless of the type of treatment and the amount of weight loss achieved. Thus, weight loss is likely not the only mechanism, and we need investigation of other potential mechanisms, those that are common to both obesity and migraine.

And so these mechanisms might be biological, for example, reductions in inflammation or improvements in cardiometabolic risk indicators. It might also be psychosocial mechanisms, such as improvements in depression, anxiety, pain acceptance, as well as behavioral risk factors that overlap these two conditions, such as physical activity, dietary composition or change, as well as improvements in sleep.

So you might be asking, if weight loss is not the primary mechanism, should headache physicians even advise patients with obesity to lose weight? And to this question, I would respond with an emphatic yes, because even modest weight loss improves sleep, mood, and other factors that increase susceptibility to having more frequent and severe attacks. Also, many of the behavioral prescriptions and recommendations that are given as part of lifestyle-modification interventions, as well as after bariatric surgery, overlap with those given for migraine management. And, finally, migraine has multiple physical and psychological comorbidities, and all of these are improved by weight loss.

So, in closing, I would first like to thank you for your attention during my talk. I’d also like to acknowledge my long list of excellent collaborators.

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Voice-over: Thank you for tuning in to Spotlight on Migraine. For more information on migraine disease, please visit MigraineDisorders.org.

*The contents of this podcast are intended for general informational purposes only and do not constitute professional medical advice, diagnosis, or treatment. Always seek the advice of a physician or other qualified health provider with any questions you may have regarding a medical condition. The speaker does not recommend or endorse any specific course of treatment, products, procedures, opinions, or other information that may be mentioned. Reliance on any information provided by this content is solely at your own risk.