Fredrick Freitag, DO

 

Slide 1. Diagnosing and Managing Hormonally Associated Migraine

This discussion will address specific management issues on menstrually associated migraine: why it is important to recognize it, and what we can do optimize management in women who struggle with the chronic condition that presents with acute episodes of disabling attacks.

Slide 2. Definitions

True menstrual migraine is a headache that occurs in women who primarily have migraine during menses. The "menstrual window" is often defined as 2 days before the onset of the menstrual flow, to 1 or 2 days after the onset of flow. Many women, however, have menstrually associated migraine.

The drop in estrogen associated with menses is a trigger factor for migraine in susceptible women. Other migraine sufferers also are susceptible to other endogenous factors, such as the onset of menarche, pregnancy, and menopause. Exogenous factors include oral contraceptives and use of hormone replacement therapy.

What do we know about menstrually associated migraine, and why do we have an interest in this process? For some patients, menstrually associated migraine may be different in its response to therapies or treatment strategies as compared with migraine that occurs outside the menstrual window.

Slide 3. Menstrual Cycle and Headache in a Population Sample of Migraineurs

One study by Stewart evaluated women who had migraine and other headache types. Specific headache types were assessed in relationship to presence of menses over a 1-month period.

Slide 4. Headaches and Menstrual Cycle

Stewart and colleagues reported that women who had migraine with aura -- where they have the well-defined visual phenomena preceding the attack by 20 to 30 minutes or so -- really showed very little difference over the course of the month in attack frequency in relation to hormone fluctuations. However, those with migraine without aura had an increase in headache frequency during the menstrual window. This study also reported that women who had tension-type headache have the same kind of phenomena.

One reason for the increase in frequency of tension-type headache that occurred during the menstrual window is that these participants might have been misdiagnosed, and they were actually migraine sufferers who thought they had tension-type or sinus headache. Additionally, some patients have 1 or 2 diagnostic criteria for migraine, but fail to meet all the criteria -- we sometimes consider these to be "migrainous headaches."

Slide 5. A View of Migraine and Menstrual Associated Migraine (MAM)

Menstrually associated migraine is a genetically determined process. If you do not have migraine headache, you do not have a sensitized trigeminal system, and the hormonal changes don't trigger the attack. However, migraine sufferers appear to have a sensitive brain that includes a sensitive trigeminal system. Hormonal fluctuations, specifically estrogen, serve as a triggering factor for eliciting the attack by altering the threshold that is required for activation of the migraine process.

Fredrick Freitag, DO

 

Slide 6. Estrogen Withdrawal

How do we know that declining estrogen levels are the precipitating factor for onset of an attack in susceptible women? We are relying on a single study done in 1972 by Somerville in Australia. He looked at a group of women who reported menstrual migraine and put them through a series of challenges, using either estrogen or progesterone. The progesterone challenge did not alter the tendency for the migraine to occur, but it did have an effect on the tendency for when menses did begin.

However, when Somerville challenged these women with a depot dose of an estrogen compound, we see that the estrogen levels change, and with it, as the estrogen levels now fall off much later because of the role of the depot estrogen, the headache occurs later.

Slide 7. Migraines Coincide With E2 Falls

Clinically, we know that estradiol levels change in relationship to the menses. Estradiol drops 1 to 2 days before the onset of the menses. Although less pronounced, there also is a decrease in estradiol during ovulation. Similarly, when women go onto the placebo days while on oral contraceptives, estradiol decreases. In the old days, when I trained, we routinely cycled women on and off of their hormone replacement therapy. Taking them off their estrogen product for the last 10 days of their cycle would trigger their migraine attacks.

Because there is going to be some variability in estrogen levels even with the patches and with the depot injections, as we get toward the end of the therapeutic range of those treatments, the decreasing estrogen levels may also be responsible, in part, for triggering migraine attacks.

Additional evidence for estrogen as a factor comes from endogenous triggers associated with pregnancy and delivery. After delivery, there is a marked decrease in estradiol concentrations, which in some women is followed by postpartum headache or migraine.

Slide 8. When Estrogen Falls

Women will often ask me, "What's wrong with my hormones that I'm getting these headaches?" There's nothing wrong with their hormones. Their hormones are behaving normally if they are having normal menstrual periods. But it is the change in hormones that elicits a variety of other physiological changes that actually precipitate and trigger this whole process of migraine.

One of the things that happens is that there is a change in concentration of the enzyme monoamine oxidase (MAO). MAO is the enzyme found in the gut and in the brain that metabolizes serotonin, which we know to be a very important neurotransmitter substance in the migraine process. This change in MAO enzyme causes a fall in serotonin levels to occur, again, setting that threshold up for transition into the migraine process.

In response to decreasing estrogen levels, there may be a change in the neural junctions with the receptors for serotonin. There is a decrease in the number of receptor sites. Postsynaptically, we see alterations in response in this reuptake of serotonin occurring because of the change in estradiol levels. Additionally, we also see a change in endorphins, the brain's natural painkillers. The brain becomes physically sensitized to pain because of this decrease in the endorphins related to the declining estrogen levels.

Slide 9. Summary: Sex Hormones and Migraine

In summary, migraine is a process that occurs in women more commonly than men, and goes through a natural history of change and effect over a woman's lifetime. During youth, boys are a little more likely to get migraine headache than girls. But with the onset of puberty (menarche), we see this epidemiology of the disorder change. After puberty, there is a higher preponderance of migraine in women. By the time we get into the middle years of life, women outnumber men with migraine by a 3:1 ratio.

Along with this, because of the effects of the estrogen changes that occur cyclically each month, we see a tendency for migraine to occur more commonly around the time of the menses. Some women who get migraine only have migraine at their menses. This is a relatively rare phenomenon, and is often referred to as "true menstrual migraine". The majority of women have hormonal factors playing a triggering role in their overall tendency to have an attack, and they will have attacks both inside and outside the menstrual window.

Slide 10. Summary: Sex Hormones and Migraine (cont'd)

A good number of women who have migraine headache have a period of remission that occurs during the last 2 trimesters of pregnancy. Part of the reason for this relates to the fluctuating estrogen levels during the first trimester. During the second and third trimester, estradiol levels are quite high and relatively stable. It is this stability in the estrogen levels that helps to induce the remission during the last 2 trimesters of pregnancy.

Slide 11. Summary: Sex Hormones and Migraine (cont'd)

During the adult reproductive years, women are exposed to hormone replacements in a variety of forms and fashions. Oral contraceptives and hormone replacement therapy can have effects, both good and bad, on the occurrence of their migraine attacks. Some women have an ablation of their migraines by taking oral contraceptives or by going on hormone replacement therapy on a steady basis in the menopausal years. Other women have a worsening of the attacks. If that occurs, it may be a signal to use an alternative compound to see if that makes a difference in the occurrence of the attacks. It is also a red flag for women who have significant changes neurologically with their migraine attacks with the start of use of an oral contraceptive or hormone replacement therapy, because these are the women who may have higher risk for complications of their migraines, such as stroke, occurring.

Thankfully, getting old does have some benefits when it comes to migraine. One of the few benefits of aging is that migraine subsides as women get older, especially as they move into their menopausal years. There is a flattening of the estradiol changes, whether because they occur naturally or because of hormone replacement therapy, and they are maintained at a set level. So we need to be sensitive to these factors in the life cycle of women and their migraine headaches.

Fredrick Freitag, DO

 

Slide 12. Management of Migraine Associated With Menses

Let us look at some of the aspects of management of migraine associated with menses.

Slide 13. Pharmacotherapy of Migraine Associated With Menses (MAM)

There are several different approaches that we can take. We can use acute therapeutics that treat the attack as it occurs, and we can use prevention to try to ameliorate propensity for the headaches from occurring at all around the menstrual period. We will look at acute treatment first.

Slide 14. The "Menstrual Window" (Varies Slightly Across Studies)

One of the challenges we face when studying and identifying menstrual migraine is defining the disorder. When is it a menstrually associated migraine attack? Based upon the clinical trial and research that is involved, there is a window that exists, from as much as 3 days before the onset of flow to as long as 5 days after the onset of flow, as being that potential menstrually associated migraine treatment window, with variability between the studies.

Fredrick Freitag, DO

 

Slide 15. Prospective Study in MAM: Sumatriptan 6 mg SC

The first of the studies that looked at menstrually associated migraine involved the injectable form of sumatriptan: a 6 mg subcutaneous dose. This was done by Facchinetti from Italy.

This group looked at the occurrence of menstrually associated migraine and its response to the injection of subcutaneous sumatriptan in a placebo-controlled trial. In this trial they had the women treat 2 migraine attacks during the menstrual window. They then looked at both 1-hour as well as 2-hour time points following the injection. Within 1 hour of treating the attack with subcutaneous sumatriptan, there was an approximately 70% response rate of reduction in headache response (decrease in pain intensity from moderate or severe to mild or none). This was quite significant vs placebo. By 2 hours, we had further improvement, approaching the 80% level of women who had a positive response with their menstrually associated migraine. Again, highly significant results vs placebo.

Slide 16. Retrospective Study With Sumatriptan 6 mg SC in MAM

A second study was done by Solbach. This was a retrospective study: they gathered chart data and looked at the response of subcutaneous sumatriptan in treating menstrually associated migraine. As in the previous study, there was a statistically significant improvement in achieving a headache response over placebo. Nausea, vomiting, and light sensitivity were markedly reduced as part of that response to the sumatriptan compared with the placebo group, which still maintained 80% of the women having photophobia 1 hour into the attack.

Slide 17. Oral Sumatriptan in MAM

One of the challenges with sumatriptan 6 mg subcutaneous is the injectable delivery. There are several different oral triptans and even nasal sprays that may prove helpful in menstrual migraine.

There are several studies to date on oral tablets, the first of which was with sumatriptan in the oral formulation. This study used the highest dose available, 100 mg.

Trial designs for migraine headache, in general, call for patients to begin treatment once the headache pain becomes moderate to severe, which is the current standard practice for clinical studies, not clinical practice.

Slide 18. Inside & Outside Menstrual Window: Response to Sumatriptan 100 mg

The first of these studies looked at attacks, not only menstrually associated, but also nonmenstrually associated. The authors report that there was a significant difference over placebo in achieving a headache response. It was not a huge difference, but if you look at the attacks of migraine that occurred during this menstrual window, by comparison with those attacks treated outside the menstrual window, there was a little over 10% difference in response rates between the 2 time frames for these individuals, and very little difference in the placebo arm of this study. It does suggest that there may be a difference in response, and that menstrual migraine requires a slightly different therapeutic approach from nonmenstrually associated migraine.

Fredrick Freitag, DO

 

Slide 19. Retrospective Review in MAM: Response to Rizatriptan 10 mg

Similar results were shown in a retrospective study with rizatriptan oral tablets. This study looked at time frame related to menses, by days in the period as well as when the attack was treated. Overall, there was a 68% response rate in the rizatriptan group, and approximately a 44% placebo response rate.

Slide 20. Retrospective Review in MAM: Response to Rizatriptan 10 mg

If we look at when in this menstrual window the migraine attack was treated with rizatriptan, on day -1 of the cycle, the day before onset of flow, the response rate was only 50%, compared with almost 70% for the entire window. This suggests that day -1 of menses is associated with a lower headache response rate, which coincides with the highest drop in estrogen levels.

Fredrick Freitag, DO

 

Slide 21. Retrospective Meta-analysis in MAM: Response to Zolmitriptan

To evaluate the efficacy of zolmitriptan, there have been 2 studies reported in the literature to date. One study was retrospective and one was prospective. The retrospective study performed a meta-analysis utilizing the data from all of the controlled clinical trials that led up to the registration and approval of the drug. There has certainly been some controversy in the headache field about how good meta-analyses are, but they certainly do serve a role. They are a standard, statistical method for looking at treatment across a variety of clinical trials.

In looking at the data retrospectively from the registration and other trials for zolmitriptan, they found that there was very little difference in response rate of those migraine attacks that were treated associated with the menses in this 3- to 5-day window compared with those attacks that were treated outside of the menstrual window. There was a little bit of favor for the 5 mg dose over the 2.5 mg dose when the attacks were inside the menstrual window.

Slide 22. Zolmitriptan in Migraine Associated With Menses (MAM)

Retrospective studies help us look for trends and identify possible clinical benefits, but, obviously, the best way to assess clinical evidence for treatment efficacy is using prospective trials. A prospective, double-blind, placebo-controlled trial with zolmitriptan was carried out utilizing a range of potential dosages based upon the intensity of the headaches. Patients used 1.25, 2.5, or 5 mg of zolmitriptan to treat migraine of mild, moderate, and severe intensity, respectively.

Slide 23. Prospective Study With Zolmitriptan: 2-hr Response in MAM

Remember, these data do not look at dosages specifically, but these women were allowed to treat based upon their severity with the dose that they thought most appropriate, from a small dose to a large dose. So they were able to gauge what kind of treatment level they should have. But in this prospective trial, we saw a very early response. About 18% of women had relief for their migraine attack within the first 30 minutes of taking their dose of oral zolmitriptan. And by 2 hours, it was about 48%. That is a little bit lower than we would expect to see, in general, from the clinical trials, but it was still highly significant compared with the placebo arm.

Slide 24. Prospective Study With Zolmitriptan: 2-hr Response in MAM

This improvement over placebo was observed at 1 and 2 hours as well.

Fredrick Freitag, DO

 

Slide 25. Pharmacotherapy of Migraine Associated With Menses

We have seen that the acute treatment is reasonably effective, and not far off the mark compared with the treatment of migraine outside of the menstrual window. Still, this is a problematic disorder if the attacks do not respond well to treatment. Therefore, we sometimes want to turn toward the preventive approach to block propensity for the attacks to occur. Several different approaches can be used along this line.

Slide 26. Naproxen Mini Prophylaxis

Probably the most common approach that we utilize for prevention of menstrually associated migraine is the use of nonsteroidal anti-inflammatory drugs taken on a mini-preventive basis, where we begin the nonsteroidal several days before the woman expects her menstrually associated migraine attack to occur. This has been looked at in a controlled clinical trial using naproxen sodium, a 550 mg dose, twice daily.

Treatment was begun about a week before the onset of the expected menstrual flow and was continued into the sixth day following the onset of flow. They did a series of treatments during successive months to evaluate the response, and it was a placebo-controlled trial.

Slide 27. Mean No. of Headache Days

This demonstrates one of the problems in doing placebo-controlled trials. If we look at a single window of opportunity, we see that in that first therapeutic month, the placebo worked as well as the active therapy -- a little disconcerting. However, with treatment over the subsequent 2 menstrual cycles, we see what would normally be expected in a placebo-controlled trial -- there is a regression of the placebo response back toward the mean. We also see that clear statistical difference occurring where there is a substantial reduction in the number of days of menstrually associated migraine occurring with the use of a nonsteroidal. Instead of having 4 days of headache, menstrually associated in a cycle, women taking the naproxen sodium 550 mg in the second and third months had about 2 days of attack. That is a nice reduction.

Slide 28. Analgesic Use

One thing that was also looked at was the effect on the use of additional medications, analgesic requirements for treating these menstrually associated migraines.

When we looked at the untreated phase there was, unfortunately, a difference between the active and placebo groups, but women in the active group required on average 4 doses of an analgesic medication per day during the menstrually associated window. With the use of the naproxen sodium, we had a drop-off to a little over 1 dose per day that was needed. So we had a very marked reduction. Again, there was an early placebo response with first cycle, but the typical regression to the mean with treating multiple attacks. One of the issues we must monitor closely is presence of gastrointestinal side effects when patients are using nonsteroidal anti-inflammatory drugs. Also, patients should be closely monitored for overuse (defined for many as using acute medications more than 2 to 3 days per week).

Fredrick Freitag, DO

 

Slide 29. Naratriptan "Mini Prophylaxis"

Using the science of nonsteroidals, what other approaches can we utilize to prevent menstrually associated migraine? One of the techniques that has become of interest and has been utilized fairly widely is to use these triptan medications, which we use acutely, as a mini-preventive approach for menstrually associated migraine. A study done using naratriptan for this purpose used 1 mg vs 2.5 mg, the standard dose, vs the placebo. They treated in the menstrual window of an approximately 5-day period of time and they treated over a series of cycles.

Slide 30. Naratriptan "Mini Prophylaxis"

Unfortunately, in this study we saw some very unusual results. First of all, the 2.5 mg dose was no more effective than placebo. Not an expected result when you are using a medication. Additionally, the lower dose was effective to reduce the number of menstrually associated migraines by approximately 50%. This was statistically significant.

However, given the cost of triptan medications and the number of attacks that were involved, the cost averaged over $300 per "headache to avoid" with this kind of treatment. It was a very expensive therapeutic when you compare it with the cost of naproxen sodium. So, we need to look at cost-effectiveness of these kinds of approaches for prevention of migraine as well.

Fredrick Freitag, DO

 

Slide 31. Hormonal Manipulation

A third approach that we utilize is hormone manipulation. This is certainly a very adequate approach for some as well.

Slide 32. Hormonal Manipulation Goals

The goal here is to change that paradigm of the drop in estradiol. We can do so by adding a supplement of estrogen perimenstrually, reducing the total falloff and keeping the other levels more constant.

Slide 33. Continuous Oral Contraceptive Therapy

We can even use oral contraceptives to do this, where we have the woman utilize the active pill packs over a series of cycles with no days off from the active therapeutic. There are different methods of doing that with different hormonal oral contraceptive compounds. This is certainly broad -- there are over 28 formulations available that we could utilize. This is a very effective method for many women who have very severe menstrual migraine.

Commonly we will have a woman cycle for 3 months on the pill before taking a cycle off. Instead of having 12 menstrually associated migraine periods a year, you now have 4, which can make a remarkable difference for many women. In Europe, the standard may be as long as a year between having menstrual flows by taking a cycle off the pill. It is really the standard of care for your practice that makes a difference here.

Fredrick Freitag, DO

 

Slide 34. Summary

In summary, the menses is a common trigger for migraine headache, because of the changes in estrogen and estradiol levels associated with normal menstrual cycles. The changes in the estrogen levels that do occur with supplemental estrogen use may again have an influencing effect for the good and therefore we all need to be sensitive to these issues.

When it comes to treating menstrually associated migraine it may be a little more challenging a disorder to treat than migraine outside of the menses, but we do know that the triptans are very effective for acute treatment of this process and can be utilized as first-line therapy. Prospective studies have specifically supported this for sumatriptan and zolmitriptan. The nonsteroidal approach is certainly a very cost-effective one, and did cause a substantial reduction in the number of attacks that were treated (caution for gastrointestinal adverse events and overuse).

For those women who may not be candidates for triptans or chose not to use acute treatments, hormonal manipulation may help bring better control and better quality of life to those women who have difficult migraine associated with their menses, especially if they are on oral contraceptive or hormone replacement therapy already.