One of the most common concerns voiced by primary care clients is most always from women, and it's the dreaded #migraine headache. Men don't have to suffer these to know their impact though, as many have witnessed their partners suffer and therefore, are familiar with their destructive nature. Migraines are the third leading cause of disability in those younger than fifty years.
Chronic migraines are less common than the random, seemingly spontaneous variety, but about one in every one hundred people do suffer migraines quite regularly. Twenty percent of visits to neurologists are to address concerns regarding migraines. Why does this happen? What can you do about it? How might a functional medicine doctor approach this differently?
It is well established that sex #hormones play an important role in migraines, which is why women of childbearing age are those who are more commonly effected. Migraines certainly do happen in men, even boys as young as five-years-old, but by adulthood, women suffer up to three times the number of migraines as men. Four of every ten women and two of every ten men will suffer at least one migraine in their lifetime, most before the age of 35 years.
Underlying Causes
More than half of women share that their migraines increase near their menses, so much so that there are several diagnoses now specific to the timing of the migraines and their association with menses. Compared to those whose menses is not specific to their migraines, women with menstrual related headaches suffer greater impairment, suffer longer, and are more likely to relapse in 24 hours, increasing the burden even further.
Several medical disorders are associated with migraines, including arterial disease, hypothyroidism, asthma, endometriosis, depression, anxiety, and somatic complaints, including fibromyalgia, chronic fatigue, irritable bowel syndrome, and interstitial cystitis. The link in all of these remains somewhat of a mystery however, yet #functional medicine practitioners are going to appreciate the overall pillars that seem to be the root cause of each of these autoimmune issues: gut health, #hormone imbalance, toxic burden, and sensitivity.
Historically, migraines were thought to be a disease of the extracranial vascular system, but today it is better understood as an inherited disorder that involves central pain modulating dysfunction among the neurotransmitters, inflammatory peptides, and vasculature modulated by the trigeminovascular system involving both the peripheral and central nervous system. This activation of the trigeminovascular system results in neurotransmission to the trigeminal nociceptors which innervate the large blood vessels in the meninges. This releases the calcitonin gene-related peptide and other vasoactive inflammatory peptides that trigger vasodilation, plasma extravagation, and further release of cytokines and proinflammatory molecules. This stimulation creates sensitization of the trigeminovascular system neurons which leads to the #pain of migraine.
Other players include nitric oxide, vasoactive intestinal peptide, Fos expression, N-methyl-D-aspartate receptors, glutamate receptors, serotonin, gamma-aminobutyric acid (GABA), prostaglandins, and pathology in the thalamus, hypothalamus, cortex or periaqueductal gray. Lots of detail there but for those of you who want to really dig into your underlying cause, understanding these may be critical for your #recovery. It is also how the functional medicine doctor thinks. We want to provide acute relief, but go further and discover the underlying etiology so we can correct the issue at its roots, providing long-term relief.
Hormones & Genetics
Functional issues are often about hormones and genetics. While genetics are not our destiny, they are more so our tendency, but our lifestyle choices and environmental health can impact this expression, which ultimately determines our hormonal health. Getting this back into balance and turning off the expression of any genetic #polymorphisms is often the focus of functional medicine.
Estrogen plays a significant role in migraines. We understand that the drop in estrogen during the luteal phase of the menses is a trigger for migraines, which is thought to result from estrogen's effect on gene expression. In women with menstrual related migraines, 17B-estradiol in physiologic doses appears to significantly reduce inflammation by reducing mRNA expression and therefore levels of CGRP, interlukenkin (IL)-1B, and inducible nitric oxide synthase (iNOS). Pharmacologic doses appear to significantly increase mRNA expression of CGRP in both patients, highlighting the differences between estrogen dose and response. Those who experience migraines have a faster late luteal phase-conjugated urinary estrogen decline which suggests an innate neuroendocrine vulnerability to #estrogen withdrawal in women with migraines.
The role of #genetics in migraine is still being investigated. Functional polymorphisms in estrogen metabolism genes COMT, CYP1A1, and CYP19A1 have not been found to be associated with menses related migraines. However, other hormone related genes have been, such as ESR1, PR PROGINS insert, and possibly, ESR2 and FSHR, as well as genetic variants in the SYNE1 and TNF genes are potentially related. Members of Eden Family Practice can find a great deal more information on how to identify these within your own genome and how to address and manage these polymorphisms to optimize your health in the Detoxification and Wellness program.
Prostaglandins are thought to also play a role. These are fatty acid derivatives of arachidonic acid and are believed to promote neurogenic inflammation and inhibit norepinephrine release. It appears that prostaglandin levels significantly increase in the luteal phase and #menstruation. Platelet abnormalities and alterations in platelet homeostasis have also been observed.
The trigeminocervical reflex mentioned previously is complex and interestingly, it seems to be stimulated or excited differently in those without migraines. During the estrogen withdrawal phase of a migraine, reduced habituation and increased pain perception to peripheral stimuli seems to occur which may partly explain why menses related migraines are more painful and debilitating.
Serotonin is yet another theory with low 5-HTP, a precursor for serotonin, being a trigger for migraine and because ovarian steroids are thought to play a role in the regulation of serotonin synthesis, low levels of enzymes which synthesis serotonin in the trigeminal ganglion may be the key to this relationship.
Approaches for Healing Menstrual Migraines
The migraines which relate to one's menses are more severe, last longer, and causes nausea and disability more so than migraines outside of the menstrual cycle, so special treatment is more often necessary. A migraine diary will be the first recommendation by your primary care provider, generally for at least 3-months, to determine the link to menstruation as well as total migraine frequency and any other patterns. A functional medicine provider will also request your diet, movement, sleep, and mood diary. A genetic evaluation will also be recommended. Once this is determined, diagnosis and treatment options are further explored.
Both pharmacologic and non-pharmacologic methods are available. Pharmacologic treatments may be those for more acute migraines or those for prevention of future migraines. Nonpharmacologic therapies are trigger avoidance, consistent sleep hygiene, hydration, exercise, and complementary treatment approaches, which will be explored a bit further.
Preventive Migraine Therapy
Preventive migraine therapy should be considered for all those who present with migraines, particularly when they are frequent (more than two a week), severe, prolonged, or hard-to-treat migraines that interfere with life activities despite correct use of acute treatment and trigger avoidance. Those who can not take effective treatment for acute migraines are also good candidates for preventive therapy.
Once titrated to the target dose, it may take eight to 12 weeks to see maximum benefit from a prophylactic medication, although some benefit may be seen within the first month. Individuals should keep a headache diary to help assess efficacy, which is often designed as a 50 percent reduction in headache days per month, but other considerations include reduction in headache severity, reduced impact on daily life, and medication tolerability. Trial and error may be required to find best option. After six to 12 months of successful use, consider a trial of tapering and discontinuing the medication.
ACEIs or ARBs such as candesartan and lisinopril are second and third-line options, or if ACEI/ARB needed for another reason such as hypertension, they they are especially perfect as a complementary pharmaceutical. These are helpful in about 25 percent of cases and typically doses are about lisinopril 20 mg once daily or candesartan 16 mg once daily.
Beta-blockers such as metoprolol, propranolol, and timolol are first-line options, especially for those who need a beta-blocker for another reason such as hypertension or angina. They work in over 40 percent of people, sometimes upwards of 80 percent, and reduce their migraines by at least half. Beta-blockers are also great for those with asthma, heart block, left ventricular dysfunction, peripheral vascular disease, and physically active clients.
Interestingly, botulinum toxins (botox) are helpful for those with 15 or more headaches per month, with headaches lasting more than four hours each day. They can cut headaches by about eight days per month, but are more helpful for chronic migraines and not as helpful for those with episodic migraines.
Calcium channel blockers, nicardipine and verapamil, are third-line with nicardipine being more effective than verapamil. The nicardipine is dosed at 20 mg once daily for three days, then 20 mg twice daily. Verapamil is dosed at 40 mg three times daily, increasing to 80 mg three times each day over one to two weeks. Maximum of 480 mg daily, divided. Can use the SR product too, divided into twice a day dosing.
Gabapentin is another option, more third-line, and great for those that may have more drug interaction concerns or who may benefit from gabapentin for other reasons. Topamax is more first-line though and can cut migraines by half. Avoid in pregnancy. Initial dose is 25 mg at bedtime, increase by 25 mg/day weekly to a target of 100 mg daily, divided twice a day or once a day for ER formulations.
Tricyclic antidepressants and valproic acid are both first-line. Consider tricyclic antidepressants for those with insomnia or depression, even tension-style headaches. Both are very effective. Amitriptyline has the most supportive data and would be dosed about 10 mg at bedtime, increased by 10 mg every one to two weeks. Target dose of 20 to 40 mg at bedtime, with max dose 150 mg per day. Nortriptyline is often used in spite of not having a lot of data to support its use.
Relief of Acute Migraines
When a client presents with an acute migraine or they have them only occasionally and are in need of relief, typically NSAIDs are recommended. Triptans are another family of medications which may be offered by prescription. Seven are currently available on the market for prescribers to choose from, and this is largely determined by the client's history of use and their specific features, such as how quickly they act and any associated benefits they may offer.
Triptans are specifically for aborting the migraine and not for prevention of future ones. They also are not effective for tension-type headaches, except in those who also suffer with migraines. They also do not offer relief for any other type of pain. They act as agonists for serotonin 5-HT receptors at blood vessels and nerve endings in the brain. The first clinically available triptan was sumatriptan, which has been available since about 1991. These medications have largely replaced a previously popular medication class, ergotamines.
Of those available, there is literature specific to frovatriptan 2.5mg, almotriptan 12.5mg, naratriptan 2.5mg, sumatriptan 6mg injectable, sumatriptan 50 and 100mg tablets (with the larger dose showing a little better efficacy). Rizatriptan 10mg and zolmitriptan 2.5mg and 5mg have also been discussed in the literature. Of these options, the frovatriptan seems to be as effective as almotriptan and zolmitriptan, but there is a lower rate of recurrence with frovatriptan because it has a longer half-life and duration of action, so it seems to be the favored option.
The NSAIDs really are a great option. As mentioned previously, one of the underlying causes seems to be related to prostaglandins which is well addressed with NSAIDs, as they interfere with their production. When the NSAIDs and triptans are combined, they have favorable outcomes. For example, adding dexketroprofen 25 or 37.5mg to frovatriptan 2.5mg offered longer relief. Sumatriptan combined with naproxen is also effective for women who are suffering menstrual cramps and a headache or migraine.
Typically with migraines, one also experiences #nausea as well, so antiemetics and prokinetics, such as a metoclopramide, may be required. Ginger may offer a safe alternative.
When we need to look at short-term prophylaxis, such as offering medication near one's menses to prevent an inevitable migraine, there are a few variables required for success. One must have a fairly regular cycle so initiation of treatment is timely. Frovatriptan has been used for this strategy as well, at the same 2.5mg dose. Typically this is provided once or twice a day for six days, starting 2 days prior to the onset of the migraine. Twice a day is the preferred approach. There are a few other options which are successful, but their dosing is more frequent than what is required of frovatriptan. Sumatriptan 25mg (Imitrex) is one example, but this is dosed three times each day, starting tow or three days prior to anticipated headache onset.
If you would prefer to utilize NSAIDs in this manner, there is some support of their effectiveness. Naproxen has been used, at 550mg twice each day, or mefenamic acid 500mg (Ponstel) three times a day for two to four days prior to anticipated onset and continued through the third day of flow, which offers relief for both cramps and migraine. If one NSAID doesn't work for you, it doesn't always mean this class of drug is ineffective, so trying another medication in the same class may be helpful.
Rebound headaches do not seem to occur with this miniprophylaxis approach. If one has a history of stroke or heart attack, uncontrolled vascular risks or hypercoagulation, then these medications would not be appropriate for you.
When long-term migraine prevention is necessary whether because one is suffering from migraines far more frequently than just around their menses, or if the above methods were ineffective, or even if abortive methods are used frequently, then daily prevention is often utilized. Two months of use is necessary before one can really determine effectiveness, so don't stop treatment too soon. It may also be helpful to somewhat increase the dose just prior to one's menses.
Medications for migraine prevention may include beta-blockers, antidepressants, antiepileptic medications, calcium channel blockers, or even botulinum toxin. When those options fail, hormonal manipulation may be considered, provided there are no contraindications such as diabetes, hyperlipidemia, hypertension, clotting disorders, or tobacco use. If one has an aura with their migraine, these are also often avoided as the risk for stroke may be increased in these clients.
The goal with hormonal treatment is to offset that steep decline of estrogen in the luteal phase that appears to be the main trigger for migraines with menses. Supplementing estrogen during the luteal phase is one approach, or using a noncycling combined oral contraceptive agent or progestin-only pill is another approach. The latter approach works by inhibiting follicular development and ovulation, thereby reducing the large estrogen fluctuation that triggers migraines. While this approach does offer a great deal of success, for some women it will worsen their migraines. This should be discussed with the client, and be aware that a new onset aura should cause immediate cessation of this treatment.
There is some literature that supports the use of estradiol gel 1.5mg starting two days prior to menses and continued for 7 days. Another study showed that a 0.1mg per day of estrogen patch starting just prior to menses and worn for 7 days was effective, but lower doses were not. Patches and gels are thought to be more effective overall because they have a more steady state of absorption compared with the fluctuations seen in oral supplementation.
If daily hormonal use is determined the best approach, the options can seem endless. The lower doses (35mg or less) of the monophasic combined contraceptive options can be among the safter options, and less disruptive to migraine sufferers. Minimizing the number of placebo days by noncycling or eliminating the placebo week, may be beneficial in reducing menses related migraines, and offers the advantage of not having a flow. The patch and ring can be helpful here as well, as they don't have the same peaks and troughs experienced with oral combinations.
The progesterone-only pill may be another option for women, which has shown to not only to improve menses related migraines, but also to address endometriosis pain. Desogestrel 75mg/day has shown to significantly reduce migraine frequency, intensity, duration, and acute treatment. More studies are needed, but for those with aura, this may be an excellent option.
There really is little information on whether inducing menopause through hysterectomy or oophrectomy is helpful in the treatment of menses related migraines. In one study, two-thirds who underwent surgical menopause actually had worse headaches, requiring postoperative use of daily estrogen.
If we look at complementary approaches, vitamin E at a dose of 400units, taken daily for five days starting two days prior to menses, has been shown to reduce both severity and disability related to migraines. This approach has also been shown to improve pain related to painful menstrual cramps as well. Magnesium has also been found to reduce the pain of a menses migraine and premenstrual symptoms.
A healthy diet and regular sleep really are paramount for avoiding migraine suffering. Maintaining proper hydration and minimizing caffeine, while avoiding triggers are additional approaches. Functional medicine practitioners can offer a number of sensitivity testings, which differ from the skin allergy testing, to help identify these triggers. Personally, Splenda is a trigger for me, causing intense migraines.
Movement, time in nature, biofeedback, meditation, icepacks and heat are other options for relief and maintenance. There are two studies which relate acetaminophen in pregnancy with ADHD and other hyperactive kinetic disorders in children, so this should be avoided if at all possible. A third study has suggested an association between acetaminophen and autism in males. More research is needed here, but limiting use certainly seems appropriate.
Often pregnant women are taught that NSAIDs are contraindicated in pregnancy, but this teaching and even this understanding by many practitioners is because it seems easier to just avoid them than to be mindful of the trimester in which they are administered. The third trimester is particularly concerning, as they may impact the function of the fetal heart, but use during earlier trimesters doesn't pose the same risk and therefore, NSAIDs maybe one of the better approaches for pregnant women. Certainly, discuss this with your practitioner. When weighing options though, consider that many narcotics which are more regularly prescribed for pregnant women, have been associated with birth defects including cardiac malformations and later addiction. Intravenous fluids may be the more simpler approach with fewer risks.
Perimenopause & Menopause
For some, perimenopause invites worsening migraines. While the average age of menopause is 51-years-of-age, perimenopause initiates sometime within that previous decade, if not even before. This transition results from declining ovarian function which results in fluctuating hormone levels. Irregular menses will trigger these fluctuations, which may also result in hot flashes, insomnia, difficulty concentrating, and a reduction in libido. Treatment can be more challenging as well, because the mini-prevention strategy is ineffective when one cannot anticipate the onset of their menses.
Interestingly, those who had a history of premenstrual syndrome seem to have a worsening transition with regards to suffering migraines. Acute strategies are first utilized, and when these are ineffective, hormone replacement therapy is typically offered if there are no other contraindications. These doses are typically lower than those one would receive with contraception. Patches and gels are less likely to aggravate migraine frequency compared with oral formulations, again, because of their steady delivery. For those with an intact uterus, the utilization of estrogen may be somewhat protective.
If migraines worsen with hormone therapy, reducing the dose may be effective, or using a non-cycling method. Switching from conjugated estrogen to pure estradiol may yet another option. If hormone therapy just isn't an option for these women, venlafaxine, paroxetine, fluoxetine, and gabapentin have also helped to reduce the vasomotor symptoms of peri-menopause, and can help with migraine prevention. Venlafaxine is likely the most effective of these options.
References
Broner, S. W., Bobker, S., & Klebanoff, L. (2017). Migraine in women. Seminars in Neurology, 37(6), 601-610.
Therapeutic Research Center. (2018). Drugs to prevent migraine in adults. Pharmacist's Letter.