After this course, the participant should be able to manage

1. (animate) Medication Overuse Headache 2. (animate) Vestibular Migraine 3. (animate) Cluster Headache 4. (animate) Hormone-related Migraine Issues

2 Medication-overuse headache, also known as rebound headache, is a headache disorder secondary to excessive reliance on acute medications to relieve recurrent headaches.

Although these terms are in common use currently, the Coalition For Headache and Migraine Patients (https://headachemigraine.org) believes the term migraine-overuse headache creates stigma by implying that the patient is to blame for taking too much medicine and the alternate term ‘Rebound Headache’ doesn’t account for the role that medication is believed to play in this type of headache. Therefore, CHAMP recommends

3 the preferred terms ‘Medication Adaptation Headache’ or ‘Medication Response Headache.’

The complex pathophysiology behind medication overuse headaches is still only partly known, but it appears that the pain medications themselves add to central chronification, or disruptive activity of the serotonergic, dopaminergic, CGRP and cannabinoid pain pathways.

This complication affects approximately ten percent of the migraine community. It occurs most commonly in middle age and affects three times as many women as men. The predisposition to this condition is not well understood.

Kristoffersen ES, Lundqvist C. Medication-overuse headache: epidemiology, diagnosis and treatment. Therapeutic Advances in Drug Safety. 2014;5(2):87-99.

3 The definition of medication overuse headache is a headache that occurs on more than fifteen days a month for more than three months, but, unlike other forms of migraine headaches, these recurrent headaches occur routinely as a pain reliever wears off. This phenomenon often strikes a person whose headaches became either more intense or more frequent. The natural reaction is to increase the use of pain relievers. Soon a person is “chasing their tail” and the drugs themselves are worsening the headaches.

While medication overuse headaches can occur with frequent use of analgesics, the effect of excessive triptan or opiate use is worse. Medication Overuse Headache is suspected when a patient reports using a nonprescription pain reliever more than fourteen days a month or a triptan, ergot or opioid medication more than nine days a month.

4 Fixing this problem can be a challenge.

The first step is to discontinue the offending rescue medicine, either “cold turkey” or as a taper. Analgesics can be weaned rapidly. For triptans and narcotics, warn the patients that they may undergo a period up to four weeks when their headaches will get worse and they may experience withdrawal symptoms of nausea, vomiting, insomnia, restlessness or constipation.

Since medication overuse headaches are a chronic form of migraine disease, most patients will need a preventive therapy treatment starting either during or immediately following withdrawal.

5 To bridge the period of time for the preventive medication to work, use prednisone with a slow taper and/or nerve blocks.

Other non-pharmacological therapies, including cognitive behavioral therapy, biofeedback, and relaxation techniques, may help to reduce pain.

In certain circumstances, inpatient treatment offers the opportunity to taper medication and use intravenous medications and other interventions under close supervision and support. It may take two to six months to break the headache cycle.

There is now hope that onabotulinumtoxinA, neuromodulation, CGRP-blocking antibodies and other new therapies will improve the treatment of this challenging condition.

5 a. Incorrect. This problem is estimated to affect closer to 10% of the migraine community. b. Incorrect. This problem affects younger, middle aged women most frequently. c. Correct d. Incorrect. Triptans should not be used or prescribed more than 9 times a month. Traditionally we have learned that when a patient complains of episodes of spontaneous spinning, nausea, ear pressure and tinnitus, the diagnosis is Meniere’s disease.

Or when a patient describes short bursts of spinning sensations with head movement, with or without nausea, we have been taught to assume that we are dealing with benign paroxysmal positional vertigo, or BPPV.

Think again. Many of these patients are, in fact, suffering from a migraine variant, vestibular migraine.

7 It has taken a long time to recognize that complaints of dizziness in many patients had any relationship with migraine disease. But clinical observations report that thirty to fifty percent of all patients with a migraine headache describe some form of vertigo or dizziness at the same time, at least occasionally. And, those with migraine headaches have three times the risk of having balance disorders.

Additionally, approximately thirty percent of all vestibular migraine attacks are not accompanied by headache. This is reminiscent of ocular migraines. What’s more, many people with vestibular migraines have had headaches in the past.

8 People with vestibular migraine report a wide range of symptoms, including spinning, both spontaneous and positional, as well as a loss of balance or lightheadedness. Spontaneous rotatory vertigo is the most common symptom with a prevalence of more than fifty percent. Positional vertigo has a similar frequency. The form of positional vertigo associated with vestibular migraine is not associated with a specific head movement as one sees with benign positional vertigo. Instead, people describe an increased sensitivity to motion, particularly movements of the head in many directions, or simply when viewing a fast-moving object.

Other symptoms include ear pressure, tinnitus, disorientation, a floating sensation, visual impairment with photosensitivity, sound sensitivity, neck pain and spasms, confusion, and increased anxiety.

But vestibular migraine not only has a wide range of symptoms from person to person, but its symptoms can vary for an individual. As with other forms of migraine, vestibular migraine can evolve from initial spontaneous rotatory vertigo into a positional form.

Another distinctive feature of vestibular migraine is the variability of

8 duration. Attacks vary from a few seconds to minutes, hours, hours, a few days or even a chronic form lasting months.

The bottom line is that there is a great deal of variability in people’s experiences with vestibular migraine

8 Vestibular migraine can occur in any period of life. But, while the onset of migraine headaches occurs during early adulthood, vestibular migraine often first appears twenty years later.

In fact, the pediatric migraine disorders of childhood, namely benign paroxysmal vertigo, paroxysmal torticollis and motion sickness, are predictive of an earlier age of vestibular migraine onset in adulthood. And vestibular migraine peaks during perimenopause, at an average age of forty-three-point-eight years.

An accurate estimate of vestibular migraine prevalence is not yet

9 possible because many physicians struggle to identify the disorder in their patients.

In 2012, one vestibular clinic identified vestibular migraine as the cause of twenty percent of the dizziness complaints, but only one- point-eight percent of the referring doctors suspected this diagnosis.

The average delay in diagnosis has been reported as eight-point- four years.

This diagnostic challenge is highlighted by the diagnostic inconsistency between specialists. A survey reported that neurologists diagnose a vestibular migraine in eighty-two percent of patients with vertigo and headache, while this opinion was shared only by sixty-four-point-five percent of otologists.

9 One important advance in the recognition of vestibular migraine was the proposed criteria for its diagnosis as a migraine subtype in the new ICHD-3 classification system.

The proposed definition of vestibular migraine is that this condition consist of moderate to severe dizziness that lasts between five minutes and three days, in a person with a current or past diagnosis of migraine headache and accompanied by some form of a migraine headache attack at least fifty percent of those times of dizziness.

Many patients will fall outside of the criteria. Until there are better

10 diagnostic tools, disagreement over who actually has vestibular migraine will persist.

It is in the best interest of our vestibular patients to ask if they have had any current, or past, history of migraine disease.

10 For our patients presenting with dizziness, let’s consider the possible causes. The differential diagnosis includes benign paroxysmal positional vertigo, often abbreviated as B--P--P--V, Meniere’s disease, labyrinth transient ischemic attacks, superior canal dehiscence syndrome, and chronic subjective dizziness. Of these, vestibular migraine, B--P--P--V and Meniere’s disease represent the most common possibilities.

Although there is still no diagnostic test to establish the diagnosis of vestibular migraine, advanced neuroimaging and vestibular testing have helped to establish with more objective evidence that it is a leading cause of dizziness and balance disorders. This Venn

11 diagram roughly estimates the relative prevalence of these three etiologies and how they may coexist in any one person.

An additional diagnostic challenge is that patients can have either vestibular migraine that mimics B--P--P--V or Meniere’s disease, or co-exists with them, only making their symptoms more variable and prolonged.

For example, the positional diagnostic Dix-Hallpike test will provoke nystagmus in seventy to one hundred percent of patients with Vestibular Migraine.

In one study, the prevalence of migraine in patients with Meniere’s disease was fifty-six percent, and the prevalence of migraine in patients with bilateral Meniere’s disease was eighty-five percent, compared to the expected rate of thirteen percent in the general public.

After understanding the high prevalence and mimicry of vestibular migraine, it is important to suspect vestibular migraine as an etiology for all balance complaints.

11 Let’s now imagine taking a history from a patient with the complaint of dizziness. When patients say “I’m dizzy”, it is important that medical professionals resist the simple solution of prescribing meclizine. Instead, let’s see if we can tease out some clues about the etiology of the complaint.

Establish what your patient means when they use the word dizzy. Is their dizziness a spinning sensation, a loss of balance or do they just feel disoriented?

If it is a spinning sensation, ask “How long does it last?” If the spinning lasts less than a minute, the next question is “Do you have spinning when you roll over in bed?” This is a question that helps to identify patients with B--P--P--V. If either rolling over does not trigger a spinning sensation or if the spinning lasts for more than a minute or two, the patient is much less likely to have B--P--P--V. For these patients, the Dix-Hallpike examination will differentiate B- -P--P--V from vestibular migraine based on the presence or absence of eye movements when their head is dropped to one side or the other.

For those patients with spinning that lasts twenty minutes to two hours, but as long as twenty-four hours, the patient may have Meniere’s disease. Ask “Have you experienced a hearing loss when dizzy?” A patient with Meniere’s disease should have an associated sensorineural hearing loss because this pathological mechanism involves a rupture of the membrane between the two fluids of the inner ear. The toxic mixture of fluids adversely affects both the vestibular and cochlear sensory systems. The dizziness of Meniere’s disease should spontaneously resolve within hours as the inner ear heals itself. But this phenomenon is known to repeat again and again in several weeks or months. If your patient’s complaints do not match with the pattern associated with the pathophysiology of Meniere’s disease, be suspicious of vestibular migraine.

If patients describe a pattern of dizziness that falls outside of those

12 of B--P--P--V and Meniere’s, it is more likely vestibular migraine. Remember that more than fifty percent of those with vestibular migraine have dizziness lasting more than twenty-four hours.

For those who do not describe their dizziness as a spinning sensation, they will have more trouble describing their symptom. You may want to ask them if their world is off-kilter, if they are having difficulty walking without veering off course, or if they are feeling lightheaded or having a rocking sensation. If they have any of these sensations they are better described as having disorientation or ataxia and these symptoms are more often associated with vestibular migraine. A favorite question is “Do you become off-balanced when walking down the aisle of a store, or in a movie theater?” If a patient experiences this problem and it is coupled with the absence of other telltale symptoms of Meniere’s disease, this person is relying on his or her visual stabilization and, when visually challenged, the mild underlying vestibular malfunction is unmasked. It is very likely that your patient has vestibular migraine.

12 Your skill in history taking is crucial because currently we lack a definitive diagnostic test for vestibular migraine. The role of testing is to reinforce your impression by ruling out other diagnoses.

To start, the value of a hearing test is to establish if a patient’s vertigo is associated with unilateral sensorineural hearing loss, a hallmark of Meniere’s disease. Migraine can also affect the cochlear nerve to cause a sensorineural hearing loss, but more characteristically in the low frequencies. And, for patients with dizziness and a sensation of ear fullness, a normal tympanogram helps to rule out middle ear disease.

13 Vestibular testing can often identify B--P--P--V, or a unilateral vestibular weakness associated with vestibular neuronitis and Meniere’s disease. In short, vestibular testing generates additional soft data that contributes to a clinical picture. One of the most common findings on testing a patient with vestibular migraine is a caloric weakness, found in up to thirty-five percent of patients. This finding suggests that migraine attacks may actually injure the inner ear. This supports the co-occurrence of vestibular migraine, B--P-- P--V and Meniere’s disease.

Vestibular testing might also have some value in predicting an individual’s response to medication. A study showed that abnormal video head impulse test (or vHIT) and abnormal caloric results correlated with a significantly greater need for continued medication after six months. These test results pointed to semicircular canal dysfunction in vestibular migraine patients and predicted prolonged preventive medication requirement. These findings also suggest that malfunctions in the sensory systems in the semicircular canals, part of the peripheral nervous system, are closely related to the pathophysiology of vestibular migraine.

Given that migraine represents a sensitive nervous system, it should come as no surprise that, when artificially stimulating the

13 vestibular system of a person with vestibular migraine, the test leaves them extremely dizzy and vomiting. Patients with vestibular migraine frequently often cannot complete of all four caloric tests, and will report they were incapacitated with a long lasting attack after testing.

13 None of us should want to experience vestibular migraine. People with vestibular migraine may have more severe symptoms than those with other vestibulopathies as well as a worse prognosis. A surveyof people with migraine headaches and vertigo had an increased frequency or intensity of: headaches, auras, nausea, vomiting, aversion to odors, allergies, sensitivity to touch, and headaches that are triggered by motion or noise, as well as an increased need for analgesics, and higher migraine disability scores than those with migraine but no vertigo symptoms. What’s more, over time, the majority of patients who go untreated do not resolve spontaneously.

Akdal G, Baykan B, Ertaş M, Zarifoglu M, Karli N, Saip S, et al. Population-based study of vestibular symptoms in migraineurs.Acta Otolaryngol.2015 May;135(5):435-439. Radtke A, von Brevern M, Neuhauser H, Hottenrott T, Lempert T. Vestibular migraine: long-term follow- up of clinical symptoms and vestibulo-cochlear findings. Neurology. 2012 Oct 9;79(15):1607–14.

14 The pathophysiology of vestibular migraine is complex and not fully understood. But there are some general principles that are supported by animal studies, genetic analysis and neuroimaging.

One, the same principles of genetic variability among those with migraine apply to vestibular migraine.

Two, there are at least eight different neurotransmitters and receptors involved in the vestibular pathways, either in the peripheral sensory organs or the central processing nuclei. These neurotransmitters include familiar names such as glutamate, serotonin and CGRP. This array of neural messengers explain the variability of vestibular migraine and offer multiple possible targets for medications. Keep in mind that, while similar to the migraine biology of pain pathways, PET scans have also revealed unique metabolic changes in the vestibular nuclei of patients with vestibular migraine that may distinguish vestibular migraine as a distinct migraine condition from other migraine syndromes.

Three, there are dense interconnections with parts of the brain controlling pain, mood, sleep, vision and more. For example, the cerebellum plays a part in processing our sense of normal balance. Dynamic roll testing has shown people with vestibular migraine are more sensitive to complex motion than those with migraine headaches only.

Four, vestibular migraine may be another chronic form of migraine secondary to neuroinflammatory damage over time. Trigeminal nerve fibers innervate blood vessels in the labyrinth. During migraine attacks, when cortical spreading depressions occur, these trigeminal fibers release inflammatory peptides in this endorgan. For example, local inflammation of the anterior vestibular artery or vestibular nerve of the utricle has been implicated as a possible cause of BPPV. Lewis RF, Priesol AJ, Nicoucar K, Lim K, et al. Dynamic tilt thresholds are reduced in vestibular migraine. J Vestib Res 2011, 21:323-330. King S, Wang J, Priesol AJ, et al. Central integration of canal and otolith signals is abnormal in vestibular migraine. Front Neurol. 2014, 5:233.

Noseda R, Kainz V, Jakubowski M, Gooley JJ, Saper CB, Digre K, et al. A neural mechanism for exacerbation of headache by light. Nat Neurosci. 2010 Feb;13(2):239–45.

Gabashvili IS, Sokolowski BHA, Morton CC, et al. Ion Channel Gene Expression in the Inner Ear. J Assoc Res Otolaryngol. 2007;8(3):305-328.

Hotchkiss K, Harvey M, Pacheco M, et al. Ion channel proteins in mouse and human vestibular tissue. Otolaryngol Head Neck Surg 2005;132:916-23.

Bisdorff AR. Management of vestibular migraine. Ther Adv Neurol Disord. 2011 May;4(3):183–91.

Ahn SK, Balaban CD. Distribution of 5-HT1B and 5-HT1D receptors in the inner ear. Brain Res.2010;1346:92–101.

Mohan A, Mohan A, Hassan-Ali, M, et al. The positive correlation between migraine and vertigo: a review. Egypt J Otolaryngol. 2016; 32(3):191-195.

Cutrer FM, Baloh RW. Migraine-associated dizziness. Headache 1992; 32: 300–304.

Shin JH, Kim YK, Kim HJ, Kim JS. Altered Brain Metabolism in Vestibular Migraine: Comparison of Interictal and Ictal Findings. Cephalalgia 2014 Jan;34(1):58-67.

Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hofman SM, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell. 1996; 87: 543–552.

Furman JM, Whitney SL. Central causes of dizziness. Phys Ther. 2000;80:179-187.

Halmagyi GM, Aw ST, Karlberg M, Curthoys IS, Todd MJ. Inferior vestibular neuritis. Ann N Y Acad Sci. 2002;956:306-313.

Su M, Yu S. Chronic migraine: A process of dysmodulation and sensitization. Mol Pain [Internet]. 2018 Apr 12 [cited 2019 Feb 12];14

15 Soto E, Vega R. Neuropharmacology of Vestibular System Disorders. Curr Neuropharmacol. 2010 Mar;8(1):26–40.

15 There is another mechanism that puts people with migraine at higher risk of chronic ataxia, or the loss of normal balance. Patients with migraine with aura frequently have silent ischemic brain lesions, often located in the cerebellum. These structural changes, as well as possibly more unseen injuries from ischemia, may be a cause of imbalance but are not necessarily related to vestibular migraine.

Bashir A, Lipton RB, Ashina S, Ashina M. Migraine and structural changes in the brain. Neurology. 2013 Oct 1;81(14):1260–8.

Kruit MC, Launer LJ, Ferrari MD, van Buchem MA. Infarcts in the posterior circulation territory in migraine. The population-based MRI CAMERA study. Brain. 2005 Sep 1;128(9):2068–77.

Demir BT, Bayram NA, Ayturk Z, Erdamar H, Seven P, Calp A, et al. Structural Changes in the Cerebrum, Cerebellum and Corpus Callosum in Migraine Patients. Clin Invest Med. 2016 Dec 1;39(6):27495.

Kellner-Weldon F, El-Koussy M, Jung S, Jossen M, Klinger-Gratz PP, Wiest R. Cerebellar Hypoperfusion in Migraine Attack: Incidence and Significance. American Journal of Neuroradiology. 2018 Mar;39(3):435–40.

Vincent M, Hadjikhani N. The Cerebellum and Migraine. Headache. 2007 Jun;47(6):820–33.

16 16 An intriguing but largely unstudied observation is that onset of menopause is marked by an increase in balance disorders. There is evidence to suggest that hormonal changes are not only a trigger of headaches but may have a more global and complex effect on the nervous system. Possible mechanisms include changes in estradiol concentrations altering metabolic activities through an effect on different receptors and through metabolites acting as either neurotransmitters or modulators.

Balthazart J, Ball GF. Is brain estradiol a hormone or a neurotransmitter? Trends Neurosci. 2006 May;29(5):241–9.

Marin R, Diaz M. Estrogen Interactions With Lipid Rafts Related to Neuroprotection. Impact of Brain Ageing and Menopause. Front Neurosci [Internet]. 2018 [cited 2019 May 4];12. Available from: https://www.frontiersin.org/articles/10.3389/fnins.2018.00128/full

17 Once we have a strong suspicion that our patients are dealing with vestibular migraine, it may be necessary to explain how their dizziness could be related to a headache disease.

One tactic is to explain that, while headache is the most common and most identifiable symptom of migraine, we should not substitute the word migraine for headache. The words we use influence how we understand this condition. Vestibular migraine, like ocular migraines, is a reminder that the migraine disease affects many parts of the nervous system and body functions, well beyond pain pathways and headaches. It may help to explain that what sets migraine headaches apart from tension headaches is that it is associated with other visual, auditory or gastrointestinal symptoms. Another tactic is to compare vestibular migraine to an ocular migraine. Like ocular migraines, vestibular migraine can occur, even in the absence of a headache.

Acknowledging the link with migraine is important because without accepting the diagnosis, patients may not be compliant with the treatment plan.

Kari E, DelGaudio JM. Treatment of Sinus Headache as Migraine: The Diagnostic Utility of Triptans Laryngoscope 118:12, 2235-2239, 2009.

18 If the patient understands that vestibular migraine is a consequence of a hypersensitive brain, it may be easier to explain that treatment depends on three principal strategies: (animate) reducing trigger If the patient understands that vestibular migraine is a consequence of a hypersensitive brain, it may make more sense to them that treatment depends on three principal strategies: reducing trigger exposure, elevating the excitation threshold and managing symptoms when they occur. One of the most effective treatments is lifestyle modification. In combination with trigger avoidance, such as dietary changes, almost all patients achieve substantial relief.

For example, by avoiding caffeine fourteen percent of patients with dizziness reported feeling less dizzy. A second strategy is to change the excitation threshold with micronutrients, also known as nutraceuticals or supplements. There are no controlled studies of the efficacy of magnesium, riboflavin, feverfew and other micronutrients for vestibular migraine, but anecdotally some commercial formulations are popular among patients.

Finally, there are both acute and preventive medications that help manage patients with vestibular migraine. Let’s now look at these options.

19 Reploeg MD, Goebel JA. Migraine-associated dizziness: patient characteristics and management options. Otol Neurotol. 2002 May;23(3):364–71.

Mikulec AA, Faraji F, Kinsella LJ. Evaluation of the efficacy of caffeine cessation, nortriptyline, and topiramate therapy in vestibular migraine and complex dizziness of unknown etiology. Am J Otolaryngol. 2012; 33(1):121–127.

19 The first instinct of a clinician is to suppress the dizziness of our patients. Many health care professionals prescribe meclizine and many patients use the nonprescription dimenhydrinate. They have antihistamine and anticholinergic properties and, while the way they reduce dizziness is not precisely known, it is likely that the major effect is the anticholinergic action in the central nervous system. For example, an antihistamine that does not cross the blood-brain barrier, such as fexofenadine, is not useful in the treatment of vertigo. Anticholinergic agents must be administered with caution in patients with asthma, glaucoma or prostate hypertrophy.

The anticholinergic agents are useful for treating milder episodes of vertigo and motion sickness, but their antihistamine effect makes them very sedating. A benzodiazepine, used in small doses, tends to control spinning sensations more effectively and may allow the patient to function better. For new-onset or brief episodes of spinning, the shorter acting lorazepam is a good choice, and it comes with the option of a dissolvable tablet for patients experiencing nausea. For those with a chronic rocking sensation, the longer acting clonazepam is a better choice. These agents work by suppressing the neurotransmitter GABA and tamping down the vestibular nervous activity. Nonetheless, benzodiazepines are controversial because of their abuse potential, risk of impaired thinking or withdrawal symptoms and, in people

20 over sixty-five, the effect is more potent and puts these patients at greater risk of confusion or falling. For these reasons, it is best to strictly use doses of zero-point-five milligrams twice daily for lorazepam or clonazepam and two milligrams B--I--D for the more sedating diazepam. The use of any one of these vestibular suppressants should be limited to a short time period under four weeks. Among the reasons for this guideline is the risk that vestibular suppressants may delay the natural compensatory process of recovery from vertigo.

Scopolamine is exclusively a cholinergic receptor antagonist. It is useful in prevention of motion sickness and can suppress persistent vestibular symptoms.

Anti-nausea medications, such as promethazine and metoclopramide, can be useful at the onset of a vestibular migraine attack. Promethazine reduces nausea but, due to its strong anticholinergic effect, it suppresses dizziness as well. Unfortunately, it also results in drowsiness.

Finally, while metoclopramide may not dampen dizziness effectively, it helps to control the associated nausea and vomiting of an attack and promotes normal gastric motility which may improve absorption of other oral drugs.

Bisdorff AR. Management of vestibular migraine. Ther Adv Neurol Disord. 2011 May;4(3):183–91.

20 Acute interventional and preventive medicines offer potentially effective nonsedating alternatives. The current literature suggests that nonprescription analgesics, especially nonsteroidals, as well as triptans may be helpful with the symptoms of vestibular migraine.

Studies have provided evidence that one-hundred milligrams of sumatriptan, ten milligrams of rizatriptan or five milligrams of zolmitriptan provide a degree of relief from dizziness, roughly equivalent to their ability to suppress headache pain, regardless of whether or not the symptoms were linked to a headache.

Obermann M, Strupp M. Current Treatment Options in Vestibular Migraine. Front Neurol [Internet]. 2014 Dec 4 [cited 2018 Mar 25];5. Available

Neuhauser H, Radtke A, von Brevern M, Lempert T. Zolmitriptan for treatment of migrainous vertigo: a pilot randomized placebo-controlled trial. Neurology (2003) 60(5):882–883. Furman JM, Marcus DA, Balaban CD. Rizatriptan reduces vestibular-induced motion sickness in migraineurs. J Headache Pain (2011) 12(1):81–88.

Cassano D, Pizza V, Busillo V. Almotriptan in the acute treatment of vestibular migraine: a retrospective study. J Headache Pain. 2015;16(Suppl 1):A114.

Maione A. Migraine-related vertigo: diagnostic criteria and prophylactic treatment.Laryngoscope.

21 2006;116(10):1782–6.

21 As a chronic form of migraine disease, the most appropriate management of vestibular migraine is preventive medicine. Dieterich M, Brandt T. Episodic vertigo related to migraine (90 cases): vestibular migraine? J Neurol. 1999; 246(10):883–892. Dieterich M, Obermann M, Celebisoy N. Vestibular migraine: the most frequent entity of episodic vertigo. J Neurol. 2016;263:82–9.

Unfortunately, a 2015 Cochrane review of preventive treatments of vestibular migraine could not identify any completed randomized controlled trials that met the review inclusion criteria.

Maldonado Fernández M, Birdi JS, Irving GJ, et al. Pharmacological agents for the prevention of vestibular migraine. Cochrane Database of Systematic Reviews 2015, Issue 6. Art. No.: CD010600

Nonetheless, preventive medications that prevent vestibular migraine can be very effective. The choices of preventive medications can be slightly different from those recommended for headaches.

Also, note that some effective vestibular migraine drugs are not available in the United States - the selective calcium channel blockers cinnarizine and flunarizine and the antihistamine betahistine.

22 In general, there are five major drug classes from which to choose. None of these medications are FDA approved for this indication. The choice of medication should be guided by its side effect profile and the comorbidities of patients.

Long-acting propranolol 60 mg per day, that may be increased as needed up to 240 mg per day, is effective, especially in younger men but at the potential loss of peak athletic performance. It runs the risk of increasing the feeling of lightheadedness in those with low blood pressure, a more common condition among women. Also, beta blockers run the risk of worsening depression, a common comorbidity with migraine. They also are not recommended for patients with asthma or diabetes.

If patients have anxiety, a tricyclic antidepressant or SNRI, such as venlafaxine XR, may be the best choice. Additionally, for those with insomnia, another common migraine comorbidity, tricyclic antidepressants can improved sleep. The downside is the risk of weight gain. Be aware that low dose of nortriptyline (90% of patients require doses of 40 mg or lower) has been observed to work better than amitriptyline and with fewer side effects.

Most people who use the SSRI venlafaxine avoid side effects but, with prolonged use, there are the risks of mood swings or fatigue.

Although lamotrigine is not the preferred antiepileptic for migraine headaches, it has proven to more effective than topiramate for vestibular migraine. Patients with concerns of weight gain may prefer this medication which is generally well tolerated.

Finally, the long-acting calcium channel blocker verapamil SR is effective but limited by the risk of constipation. It also is more risky in patients over 55 years of age - a large constituency of the vestibular migraine population.

To get a sense for how effective these medications can be, a review of 156 patients showed that 46% of patients had a reduction in dizziness after nortriptyline therapy, in contrast to a 25% improvement with topiramate.

22 Mikulec AA, Faraji F, Kinsella LJ. Evaluation of the efficacy of caffeine cessation, nortriptyline, and topiramate therapy in vestibular migraine and complex dizziness of unknown etiology. Am J Otolaryngol. 2012 Feb;33(1):121–7.

In a separate study of 2 vestibular migraine preventive drugs, used for 4 months, both propranolol and venlafaxine were equally efficient in nearly resolving vertigo attacks, but venlafaxine appeared to be superior in relieving comorbid depressive symptoms.

Salviz M, et al. Propranolol and venlafaxine for vestibular migraine prophylaxis: A randomized controlled trial. Laryngoscope. 2016;126:169–174

In conclusion, one approach is to simplify your choices to nortriptyline, venlafaxine XR or lamotrigine.

Bisdorff AR. Management of vestibular migraine. Ther Adv Neurol Disord. 2011 May;4(3):183–91. Baier B, Winkenwerder E, Dieterich M. “Vestibular migraine”: effects of prophylactic therapy with various drugs. A retrospective study. J Neurol.2009; 256(3):436–442. Bikhazi P, Jackson C, Ruckenstein MJ. Efficacy of antimigrainous therapy in the treatment of migraine- associated dizziness. Am J Otol. 1997; 18(3):350–354. Maione A. Migraine-related vertigo: diagnostic criteria and prophylactic treatment. Laryngoscope. 2006; 116(10):1782–1786.

THESE ARE NOTES - not part of the voice-over Verapamil L type Ca2+ channel blocker Management of vertigo of peripheral origin Verapamil for vertigo and related disorders. Timothy C. Hain, MD Last update: December 12, 2015 IndexPlease read our disclaimer. The main two disorders where verapamil is used are migraine and meniere's disease -- two closely related "committee" diagnoses. In other words, these two disorders overlap heavily, are diagnosed using entirely subjective criteria, and could even be

22 often two faces of the same illness. The usual dose of verapamil is 120 to 240 mg, SR, once per day. SR means sustained release. This drug is an dihydropyridine L-channel calcium channel blocker, similar to other dihydropyridine drugs like nifedipine, nimodipine and diltiazem. Verapamil is modestly effective for migraine but it takes about 2 weeks to work, and dose may need to be escalated too requiring more time. According to Davidoff (2002), doses as high as 480 mg/day may be necessary for migraine. Verapamil is effective in migraine variants such as hemiplegic migraine (Yu and Horowitz, 2003; Davidoff 2002), perhaps because of the pathophysiology of hemiplegic migraine that can involve the calcium channel receptor. Compared to beta-blockers, verapamil is less effective for common migraine (Davidoff, 2002). Verapamil also may be helpful in Menieres disease, although this has not yet been documented by a controlled study. A close relative to verapamil, Nimodipine has been reported to be helpful for Meniere's disease (Lassen et al, 1996). Neither of these medications are used commonly in Meniere's. Meniere's disease is plagued by reports of treatments that are initially thought to be helpful, but later inseparable from placebo. This is due the extreme variability and relative infrequency Meniere's, making it easy to be fooled. See this link for more. Meniere's and migraine are close relatives. Side effects About 50% of users of verapamil develop mild constipation. We like to combine verapamil prescriptions with oral magnesium supplements (500 mg/day), as magnesium has some tendency to counteract the constipation and is also a prevention medication for migraine. (Holland, 2012) Sometimes verapamil lowers blood pressure but this is generally not a big problem if it is started gradually. About 1% of users develop palpitations (fluttering feeling in chest). Stop taking this drug if you develop palpitations. A few individuals develop swelling of the ankles. Verapamil is safe in patients with asthma, and especially good in patients who also have high blood pressure. Should start with dose mg. roughly = weight of patient (in pounds). Verapamil has no cognitive side effects and no effect on weight. Some studies even reported that calcium channel blockers enhance cognition (Kowalska and Disterhoft, 1994). However, this observation has not stood the test of time. Other Precautions and Concerns There are several concerns about verapamil that should limit its use. Because of studies suggesting increased mortality from heart disease, verapamil and related

22 drugs in the calcium channel blocker family are not favored in individuals aged 55 and older. Verapamil is one of the drugs favored for treatment of cluster headache in pregnancy and lactation (Jurgens et al, 2009). One study suggested an increased risk of cancer (about 2 fold) in persons taking verapamil in Rotterdam (Biederbeck-Noll et al, 2003). However, the study of Dong et al (1997) included 11,000 patients in all published trials at the time and found "There is no statistically significant increased risk of cancer or deaths with verapamil compared with active controls or placebo." We think the much larger and more geographically diverse study of Dong is more likely to be correct than a smaller study done in a single country. As verapamil is often associated with constipation, and constipation increases the risk of colon cancer, one could speculate that verapamil might increase the risk of colon cancer. However, if one keeps the constipation under control with diet or appropriate laxatives, this risk should be nonexistent. Verapamil increases blood levels of simvistatin (Kantola et al, 1998). Doses of simvistatin should be reduced to 10mg when verapamil is also prescribed. Statins also increase the bioavailability of verapamil (Choi et al, 2010), and when a statin and verapamil are combined, doses of verapamil should also be decreased. References: Bartual J, Vidal J, Magro E, Roquette J. Effects of cinnarizine plus dihydroergocristine in 122 patients with cervical vertigo. Current Therapeutic Res, 46, 6, 1989, 1196- 1202. Beiderbeck-Noll, A. B., et al. (2003). "Verapamil is associated with an increased risk of cancer in the elderly: the Rotterdam study." Eur J Cancer 39(1): 98-105. Choi, D. H., J. H. Chung, et al. (2010). "Pharmacokinetic interaction between oral lovastatin and verapamil in healthy subjects: role of P-glycoprotein inhibition by lovastatin." Eur J Clin Pharmacol 66(3): 285-290. Davidoff RA. (2002) Migraine manifestations, pathogenesis and management (2nd edn). Oxford, page 408 Dong, E. W., et al. (1997). "A systematic review and meta-analysis of the incidence of cancer in randomized, controlled trials of verapamil." Pharmacotherapy 17(6): 1210- 1219. PSCS Health Systems Clinical Pharmacy Review, vol 7, #1. Eli Lily. Greenberg DA. Calcium channels in neurological disease. Ann Neurol 1997;42:275- 282. Holland, S., et al. (2012). "Evidence-based guideline update: NSAIDs and other

22 complementary treatments for episodic migraine prevention in adults: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society." Neurology 78(17): 1346-1353. Jurgens, T. P., et al. (2009). "Treatment of cluster headache in pregnancy and lactation." Cephalalgia 29(4): 391-400. Kantola, T., K. T. Kivisto, et al. (1998). "Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations." Clin Pharmacol Ther 64(2): 177-182. Kowalska, M. and J. F. Disterhoft (1994). "Relation of nimodipine dose and serum concentration to learning enhancement in aging rabbits." Exp Neurol 127(1): 159- 166. Kristensen, S. D., et al. (1983). "Verapamil does not alter platelet function in patients with recent myocardial infarction." Thromb Res 32(4): 437-442. Lassen LF, Hirsch BE, Kamerer DB. Use of nimodipine in the medical treatment of Meniere's disease: clinical experience. Am J Otol. 1996 Jul;17(4):577-80. PMID: 8841703 Radtke, A., et al. (2002). "Migraine and Meniere's disease: is there a link?" Neurology 59(11): 1700-1704. Rassekh, C. H. and L. A. Harker (1992). "The prevalence of migraine in Meniere's disease." Laryngoscope 102(2): 135-138. Yu W, ZHorowitz S. Treatment of sporadic hemiplegic migraine with calcium-channel blocker verapamil. Neurology 2003:60:120-121

Medication When medication becomes necessary, otolaryngologists often have their favorite standbys as first-line treatments. Experts, however, said several considerations are warranted regardless of the regimen. Dr. Foster said she tailors prophylactic medications to the severity and full suite of a patient’s symptoms, as well as the side- effect profiles of candidate drugs. Dr. Semaan recommended starting the medication slowly and increasing the amount based on the patient’s tolerance, then staying with the medication for at least six months before tapering back down. For more severe cases of vertigo, especially those that don’t respond to a first or second-line drug, otolaryngologists said involving a neurologist is always a good idea. For a first or second-line therapy, common drugs of choice include verapamil (Calan) and the tricyclic antidepressant nortriptyline (Pamelor). For verapamil, “We use it in a very low dosage, below levels that we would use for blood pressure control,” said

22 Aaron Benson, MD, clinical adjunct professor of otolaryngology head and neck surgery at the University of Michigan and Michigan State University. “I find that to be very effective in my patients and it has the lowest side effect profile of the medications that I can normally offer to patients,” said Dr. Benson, also medical director of the Ohio Hearing and Balance Institute at St. Luke’s Hospital in Maumee. Dr. Foster agreed, noting that verapamil is a good choice for patients with hypertension or arrhythmias. How the drug works is less clear, especially in light of the uncertain etiology of migraines. One hypothesis suggests symptoms may be related to a vasospasm of the blood supply to the posterior fossa. Another posited that the condition results from a disruption of calcium ion channels. Either way, Dr. Benson said calcium channel blockers make sense as a first-line therapy. “A calcium channel blocker relaxes vessels so it would work if it’s vasospasm, and if it’s a calcium ion channel problem, well, it’s a calcium channel blocker,” he said. “I find that to be an extremely effective medication.” Dr. Goebel often starts with the relatively inexpensive nortriptyline, which he prefers over its chemical cousin amitriptyline (Elavil) because it is less sedating and patients aren’t as likely to gain weight. Dr. Foster noted that amitriptyline’s sedative effect can be a plus for patients with poor sleep patterns, thereby also removing lack of sleep as a potential migraine trigger. Other side effects can include dry eyes and a dry mouth, and both drugs are usually contraindicated for pregnant women. The potential mechanism for action by tricyclic antidepressants in addressing migraine is poorly understood, though some researchers suggest that regulation of the serotonin neurotransmitter may play a role. Experts also note that antidepressants have been widely used for pain control. New Options Among the few promising new drugs, Dr. Foster pointed to Namenda (memantine), normally used to treat Alzheimer’s disease. The drug seems to work best in cases with prominent aura, she said, when the inner ear may be damaged by low blood flow, by blocking the NMDA [N-methyl-D-aspartate] receptor calcium channel. That channel is involved in excitotoxicity, or the death of nerve cells from excessive stimulation, a pathway that Dr. Foster has been exploring as the mechanism for severe attacks. “If you can block excitotoxicity, you can block the damage,” she said. “So for people with progressive damaging disorders who have migraine, blocking that kind of damage then prevents the disorder from progressing.” Patients with uncontrolled migraine-associated vertigo who had failed other drug treatments found relief with the drug, Dr. Foster said. “But this is really early, so we

22 don’t know yet what the difficulties that we’re going to encounter with the drug are.” Specialists agreed that other potent drugs like topiramate (Topamax), used to treat seizures in epilepsy patients, should likewise be reserved as a third-line option if other regimens fail. Dr. Goebel cautioned that he’s encountered cognitive problems among some patients on the drug. “You get some word-finding problems, not being able to exactly come up with the word you want to use,” he said. Similarly, beta blockers like propranolol (Inderal) may be effective but can have a significant downside. “The problem with Inderal as a beta blocker is that if you give it to a younger person, not only does it lower their blood pressure, but it lowers their exercise tolerance,” Dr. Goebel said. Dr. Foster also uses propranolol sparingly, but noted that it can be a good choice for migraine patients with tremor or high blood pressure. A similarly intense medication like the anti-epileptic and altitude sickness drug acetazolamide (Diamox) may likewise help in more severe cases, Dr. Foster said, such as vertigo with damaging hearing loss. Diamox, Inderal and the occasionally prescribed anti-seizure medication lamotrigine (Lamictal) may not stop headaches, though, potentially requiring such patients to take more than one drug. Experts have pointed to some limited success with the depression and generalized anxiety disorder drug escitalopram (Lexapro), although the medication is prescribed primarily by neurologists. Another small randomized clinical trial pointed to zolmitriptan (Zomig) as a somewhat beneficial abortive treatment, a rarity among triptans. And an observational study found marginal improvement with the blood pressure medication metoprolol (Lopressor, Toprol) (J Neurol. 2009 256(5):711-716). The take-away lesson, otolaryngologists say, is that a suite of symptoms still in search of clear categorization may nevertheless respond to a carefully chosen, individually tailored treatment regimen that stops the spinning world of vertigo patients. ENTtoday - https://www.enttoday.org/article/a-personal-spin-on-migraine- associated-vertigo-treatments-with-few-formal-guidelines-otolaryngologists-use- trial-and-error/ Betablockers such as propanolol or metoprolol are preferred in patients with hypertension but in the absence of asthma. Anticonvulsants include topiramate when patients are obese, valproic acid and lamotrigine. Lamotrigine is preferred if vertigo is more frequent than headaches. Calcium antagonists include verapamil and flunarizine. If patients have anxiety, tricyclic antidepressants such as amitryptiline or nortryptiline or SSRIs and benzodiazepines such as clonazepam are recommended. Acetazolamide is effective

22 in rare genetic disorders related to migraine-like episodic ataxia; however, its place in vestibular migraine is still to be established. Nonpharmacological measures such as diet, sleep, hygiene and avoidance of triggers are recommended as they are for migraine. Vestibular rehabilitation might be useful when there are complications such as loss of confidence in balance or visual dependence. not entirely clear why they are helpful (i.e. whether it is the calcium channel blocking effect or some other effect), as well as in which group of patients they might be helpful. A positive interpretation of these studies is that the vestibular system, either peripherally or centrally, uses calcium channels, and that these drugs block them, causing vestibular suppression effects. There is good evidence for calcium channels peripherally, which are predominantly the L-type (Fuchs et al., 1990; Zidanic & Fuchs, 1995). In the periphery, Perin and others reported that in frog, all calcium channel blockers tested reduce resting rate and that L-channel blockers, such as nimodipine, nifedipine, and perhaps verapamil, reduce mechanically evoked activity (2000). Reducing the resting rate might reduce spontaneous nystagmus and reducing mechanically evoked activity might correlate with reduction in movement-induced symptoms. They suggested that L-type channels were involved in hair cell synaptic transmission and that another receptor was also involved with modulating afferent firing (2000). Centrally, Serafin et al (1990, 1991) have demonstrated the existence of high- threshold (L or N type) and low-threshold (T-type) calcium channels in the vestibular nucleus. Davidoff discussed two hypotheses why calcium-channel blockers might prevent migraine (2002). The first hypothesis is that there are actions on neurons, and furthermore that the agents enter the brain (to affect the neurons). This likely varies according to the agent. The second theory is that calcium-channel blockers block vasoconstriction through their effects on smooth muscle. There are major problems with this theory, according to Davidoff. A negative interpretation is that these are sloppy drugs, and their vestibular suppressant effects are related to slop -- antihistamine or anticholinergic activity, or perhaps just sedation. In support of the idea that the calcium channel effect is not important, Sansom et al (1993) reported that L-type calcium channels do not contribute to static vestibular function in the guinea pig vestibular nucleus (Sansom et al, 1993). However, if L-type blockers affect the periphery as Perin et al reported (2000), the lack of effect on the vestibular nucleus only means that these drugs do

22 not act there. A third possibility is that some of these drugs are good anti-migraine agents, and they work when migraine is mixed in with Menieres. The reality is probably a mixture of all three. Calcium channel blockers also have numerous other effects beyond their effects on dizziness. They are generally negative inotrophic agents, which means that they decrease how strongly the heart pumps. Some of them are anti-apoptotic -- in other words, the reduce programmed cell death. The flip side of this is they may slightly increase cancer. In the Syst-Euro trial, nitrendipine (a long-acting dihydropyridine) was found both cardioprotective as well as reduced the prevalence of dementia by 50%. The 50% figure is difficult to believe. Nimodipine also has been reported to improve learning in aged rabbits (Kowalska and Disterhoft 1994). Verapamil is protective in an animal model against kanamycin ototoxicity (Zhuravskii et al. 2002) Other long-acting dihyropyridines in the US are amlodipine, felodipine, nicardipine, and long-acting nifedipine. Amlodipine (Norvasc). Amlodipine is an inexpensive and commonly used calcium channel blocker, generally prescribed to treat hypertension. There is weak evidence that it is helpful for migraine (Davidoff, 2002). Cinnarizine (not available in USA) Diltiazem (Cardizem). According to Davidoff (2002, page 409), diltiazem has been found helpful in small pilot studies, for migraine. We have not found diltiazem helpful, and in fact, we usually suggest that patients replace it with verapamil when attempting to treat migraine. Flunarizine (Sibelium, not available in USA) Lee et al (86) reported that Flunarizine is a vestibular suppressant. The main effects of flunarizine seem likely to be more due to dopamine blocking than calcium channel blocking. Flunarizine is not FDA approved in the USA, in part, due to it's tendency to induce parkinsonism. Gabapentin (Neurontin) This poorly named drug which looks somewhat biochemically like GABA, does not interact with the GABA receptor, but rather has a high binding affinity for the Ca(2+)- channel subunit alpha(2)delta, and is a calcium channel blocker. We don't find gabapentin to be especially useful for dizziness, but it can sometimes suppress

22 nystagmus, even of the congenital variety. Nifedipine (Procardia) Nifedipine is a vasodilating calcium channel blocker that has more side effects than most other calcium channel blockers. There is no reasonable rationale for its use in migraine (Davidoff, 2002). We don't find nifedipine useful for dizziness either. Nimodipine (Nimotop) Nimodipine is an expensive calcium channel blocker, marketed largely for treatment of subarachnoid bleeding. It has been used for Menieres disease(Lassen et al, 1996), as well as peripheral vertigo (Pianese et al, 2002) with positive results. It is not effective in migraine (Davidoff, 2002). Nimodipine clearly enters the brain to a greater extent than many other calcium channel blockers. If this were an important feature, one would expect that nimodipine would be the most effective of these agents. As this is not true, it seems likely direct effect of calcium channel blockers on neurons is an unlikely mechanism for positive effects of the other agents. Oddly, nimodipine appears to help learning in elderly rabbits (see below). The bottom line is that we see no reason to prescribe this drug instead of the cheaper verapamil (see below). Kowalska, M. and J. F. Disterhoft (1994). "Relation of nimodipine dose and serum concentration to learning enhancement in aging rabbits." Exp Neurol 127(1): 159- 166. Verapamil (Available) -- See the link above. References: Bartual J, Vidal J, Magro E, Roquette J. Effects of cinnarizine plus dihydroergocristine in 122 patients with cervical vertigo. Current Therapeutic Res, 46, 6, 1989, 1196- 1202. Davidoff RA. (2002) Migraine manifestations, pathogenesis and management (2nd edn). Oxford Doweck I, Gordon CR, Spitzer O, Melamed Y, Shupak A. The vestibulo-ocular reflex (VOR) under the influence of cinnarizine. J. Vest Res 4, 3, 215-220, 1994. Fuchs, PA., Evans, MG. & Murrow, BW. (1990). Calcium currents in hair cells isolated from the cochlea of the chick. Journal of Physiology 429, 553-568. Greenberg DA. Calcium channels in neurological disease. Ann Neurol 1997;42:275- 282. Hahn, A., I. Sejna, et al. (2008). "A fixed combination of cinnarizine/dimenhydrinate for the treatment of patients with acute vertigo due to vestibular disorders : a

22 randomized, reference-controlled clinical study." Clin Drug Investig 28(2): 89-99. Lassen LF, Hirsch BE, Kamerer DB. Use of nimodipine in the medical treatment of Meniere's disease: clinical experience. Am J Otol. 1996 Jul;17(4):577-80. PMID: 8841703 Lee JA, Watson LA, Boothby G. Calcium antagonists in the prevention of motion sickness. Aviat Space Environ Med 1986:57:45-8. Olesen J. Calcium entry blockers in the treatment of vertigo. Ann N Y Acad Sci. 1988;522:690-7 Pianese CP eand others. New approaches to the management of peripheral vertigo: efficacy and safety of two calcium antagonists in a 12-week, multinational double- blind study. Otol and Neurotol. 23:357-363, 2002 Perin P and others. Calcium channels functional roles in the frog semicircular canal. NeuroReport 11:417-420, 2000 PSCS Health Systems Clinical Pharmacy Review, vol 7, #1. Eli Lily. Pytel, J., G. Nagy, et al. (2007). "Efficacy and tolerability of a fixed low-dose combination of cinnarizine and dimenhydrinate in the treatment of vertigo: a 4-week, randomized, double-blind, active- and placebo-controlled, parallel-group, outpatient study." Clin Ther 29(1): 84-98. Rascol O, Clanet M, Montastruc JL. Calcium antagonists and the vestibular system: a critical review of flunarizine as an antivertigo drug. Fundam Clin Pharmacol 3 (1989) 79s-87s. Sansom AJ, Smith PF, Darlington C. Evidence that L-type calcium channels do not contribute to static vestibular function in the guinea pig vestibular nucleus. rain Res 630 (1993), 349-352 Scholtz, A. W., M. Schwarz, et al. (2004). "Treatment of vertigo due to acute unilateral vestibular loss with a fixed combination of cinnarizine and dimenhydrinate: a double-blind, randomized, parallel-group clinical study." Clin Ther 26(6): 866-877. Serafin M et al. Low threshold calcium spikes... Exp Br Res 82(1990) 187-191. Serafin M et al. Medial vestibular nucleus ... Exp Br Res 84(1991), 426-433 Tolu E, Mameli O (1984). Pharmacological improvement of vestibular plasticity effects of a Ca2+ antagonist agent. Pharmacol Res Commun 16, 1161-117 Tolu E, Mameli O, Melis F, Caria MA. Role of Ca2+ entry blocker Flunarizine in vestibular compensation. Post-lesion neural plasticity (H. Flohr, Ed), Springer-Verlag, 1988 Tolu E, Mameli O, Caria MA, Melis F. Improvement of vestibular plasticity in the guinea pig with a calcium entry blocker. Acta Otolaryngol (Stockh) 1988:460:72-79

22 Turner, D., Y. Lurie, et al. (2006). "Pediatric cinnarizine overdose and toxicokinetics." Pediatrics 117(5): e1067-1069. Zhuravskii SG, Lopotko AI, Tomson VV, Ivanov AG, Chomskii AN and Nurskii KV (2002). "Protective effect of calcium channel blocker verapamil on morphological and functional state of hair cells of the organ of corti in experimental kanamycin-induced ototoxicity." Bull Exp Biol Med 133(4): 404-7. Zidanak, M. & Fuchs, PA. (1995). Kinetic analysis of barium currents in chick cochlear hair cells. Biophysical Journal 68, 1323-1336. © Copyright December 18, 2016 , Timothy C. Hain, M.D. All rights reserved. Last saved on December 18, 2 Bisdorff AR. Management of vestibular migraine. Ther Adv Neurol Disord. 2011 May;4(3):183–91.

22 Vestibular rehabilitation, which is a series of repeated head and eye movements that help the brain adapt to, or compensate for, a malfunctioning balance system, has been shown in a large review to be inconclusive in its efficacy to improve either vestibular or headache symptoms. Since patients with vestibular migraine are hypersensitive to motion stimulation, they will usually find vestibular rehabilitation difficulty to tolerate. Nonetheless, select patients with an uncompensated vestibulopathy, B--P--P--V, loss of confidence in balance or visual dependence, might benefit from a professional therapist. As a general rule, it is recommended to control patient symptoms as best as possible with medication before adding vestibular rehabilitation and then start and progress slowly with exercises.

Bisdorff AR. Management of vestibular migraine. Ther Adv Neurol Disord. 2011 May;4(3):183–91. Sugaya N, Arai M, Goto F. Is the Headache in Patients with Vestibular Migraine Attenuated by Vestibular Rehabilitation? Front Neurol [Internet]. 2017 Apr 3 [cited 2018 Apr 10];8. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5377541/ Vitkovic J, Winoto A, Rance G, Dowell R, Paine M. Vestibular rehabilitation outcomes in patients with and without vestibular migraine. J Neurol. 2013 Dec;260(12):3039–48. Herdman SJ. Vestibular rehabilitation. Philadelphia: F.A. Davis Co.; 1994 Shepard NT, Telian SA. Practical management of the balance disordered patient. San Diego: Singular Publishing; 1997. Alghadir A, Anwer S. Effects of Vestibular Rehabilitation Migraine: A Review. Frontiers in Neurology. 2018;9. One other distinctive balance disorder is Mal de Debarquement syndrome, more easily abbreviated to M--D--S. This is a French term that can be loosely translated to an illness after disembarking, presumably from a boat. The “illness” is a prolonged feeling of unsteadiness or gently rocking after being on a boat. It is believed that a long exposure to passive motion is the trigger or cause. Patients with motion-triggered M--D--S often develop new onset headaches. But the onset of M--D--S has been observed to occur without a motion trigger. More than forty percent of both groups have migraine headaches. Though rocking dizziness does not meet current criteria for vestibular migraine, migraine physiology may predispose to, develop in, or worsen with the onset of chronic rocking dizziness.

This rocking sensation often resolves spontaneously, but for those with persistent symptoms, the first line drug is low-dose clonazepam, zero-point- two-five milligrams twice daily. Higher doses are no more effective. While this medicine does not completely relieve the rocking sensation, it tends to allow people a more normal lifestyle. It should not be used for more than a month. The next choice would be a selective serotonin reuptake inhibitor.

Cha YH, Cui Y. Rocking dizziness and headache: a two-way street.Cephalalgia.2013 Oct;33(14):1160-1169.

24 Cha YH. Mal de Debarquement. Semin Neurol. 2009 Nov;29(5):520–7.

24 True or False

1. True. Currently the most frequent vestibular symptoms are spontaneous rotatory vertigo and positional vertigo, but vestibular migraine is also marked by a spectrum of dysequilibrium symptoms.

1. False. Blood vessels in the inner ear do play a part in vestibular migraine.

1. False. Triptans can be effective in vestibular migraine but not as reliable as when used to stop migraine headaches.

1. True. Nortriptyline, verapamil, propranolol, topiramate, clonazepam and venlafaxine may play a role in the prevention of vestibular migraine. Cluster headaches are distinctive from traditional migraine headaches. They are usually unilateral, very, Very (intentional repetition of the word) intense pain located typically around the eye. The pain can be a burning or stabbing sensation. The episodes of pain can be as short as fifteen minutes or can last longer than three hours. Some migraine-like symptoms — including sensitivity to light and sound and nausea — can occur with a cluster headache.

Distinctive features include: one, average episodes lasting forty-five to ninety minutes, making them shorter than migraine headaches; two, autonomic symptoms, such as nasal congestion, runny nose, eyelid swelling or drooping and red watery eye; three, all of these symptoms typically are confined to one side of the head; four, in contrast to people with migraine headaches who often find relief by going to sleep, those with cluster headaches awaken from sleep with pain and are very restless and prefer to pace or sit and rock back and forth; and five, the episodes usually recur over and over again. They are called cluster headaches because patients experience an episode one to twelve times per day during a period of time (the cluster cycle), which may last from one week to twelve months, but most commonly one to three months. People with cluster headaches usually have periods of remission when they are pain free for months, but about ten to fifteen percent of chronic cluster patients never get a break.

26 The triggers for cluster headaches are somewhat different from those of a migraine headache. They include alcohol, cigarette smoke, coffee, foods high in nitrites (such as bacon and preserved meats), high altitudes (such as flying or hiking), bright light (including sunlight), physical activity, and heat (such as hot weather or hot baths). Cluster headaches affect less than zero-point-two of the general population and men are more commonly affected than women at the rate of three to one. You will see about one-hundred-twenty patients with migraine for every patient with cluster headache. Due to the intensity of pain, those with cluster headaches have a suicide rate twenty times higher than the national average. The clinical presentation of cluster attacks suggests that this neurovascular disorder affects the trigeminal pain pathways, the autonomic system and the hypothalamus, where the biological clock and neuroendocrine systems are regulated. Advanced neuroimaging locates neural activity in the posterior hypothalamic grey matter during a cluster attack. The full understanding of what generates this activity and how to control it is yet to be discovered. The diagnosis of cluster headache can be difficult because the presentation may resemble one of the trigeminal autonomic cephalalgias, trigeminal neuralgia or dental pain. For the dental community to whom patients can complain bitterly of dental pain, it is so important to keep the diagnosis of migraine or cluster in mind as both can produce phantom tooth pain or T--M--D. But, since cluster headaches appear to have a distinct neurobiology, they do not respond to many migraine drugs.

Multidisciplinary Association for Psychedelic Studies website Lantéri-Minet M. Pathophysiology of cluster headache. Rev Neurol (Paris). 2003;159(12):1113–1124.

Evers S, Afra J, Frese A, et al. Gilhus NE, Barnes MP, Brainin M, editors. Cluster headache and other trigemino-autonomic cephalgias. European handbook of neurological management 2nd edn, 2011, Oxford, UK: Blackwell Publishing Ltd

May A. Cluster headache: Pathogenesis, diagnosis, and management. Lancet 2005; 366: 843–855.

Table adapted from Hattle AS. Cluster Attacks: A Guide to Surviving One of the Most Painful Conditions Known to Man For Patients, Supporters & Health Care Professionals. 2017 p.22 image from Cluster headache [Internet]. Tidsskrift for Den norske legeforening. [cited 2019 May 6]. Available from: https://tidsskriftet.no/en/2015/08/cluster-headache

26 Cluster headache is a distinct brain disorder involving only one of the two trigeminal nerve bundles, usually its second branch which innervates the mid-face. The condition also involves the associated autonomic nerve fibers which account for the nasal congestion, runny nose, eyelid swelling, and red watery eye.

While cluster attacks are related to migraine disease, they appear to be centered in a different set of nerve centers, or nuclei, within the brain - the hypothalamus and suprachiasmatic nucleus. This set of nerves is associated with the body’s daily timing of activities, such as sleeping and waking, and is consistent with the circadian rhythms of cluster attacks.

This distinction in neurobiology also may explain the unique patterns of attacks, their intensity, the patient’s restlessness rather than fatigue and patient response to different treatments.

Cluster headache [Internet]. Tidsskrift for Den norske legeforening. [cited 2019 May 6]. Available from: https://tidsskriftet.no/en/2015/08/cluster-headache

27 There are three treatment strategies: interventional, transitional and preventive.

The most effective interventional, or abortive, treatments for cluster headache attacks are six milligrams of injectable sumatriptan, breathing one hundred percent oxygen through a face mask for twenty minutes or five to ten milligrams of zolmitriptan nasal spray. Triptans are limited by cardiovascular disease and oxygen therapy can be inconvenient. In 2019 the FDA approved the use of vagus nerve stimulation in the acute treatment of episodic cluster headache.

Secondary options include a short course of corticosteroids, ergotamines or a sphenopalatine ganglion block. https://www.medgadget.com/2017/07/non-invasive-gammacore-device-fight-pain-cluster-headaches- released-u-s.html

Ekbom K, Monstad I, Prusinski A, et al. Subcutaneous sumatriptan in the acute treatment of cluster headache: A dose comparison study. The Sumatriptan Cluster Headache Study Group. Acta Neurol Scand.1993; 88: 63–69.

28 Transitional treatment is a strategy that, unlike a short-acting interventional medicine, provides rapid reduction in attack frequency during a short period of time until a long-duration prophylactic agent takes effect. Therefore, transitional and maintenance prophylaxes are often started simultaneously.

The most common oral option is prednisone. The common daily dosing of one milligram per kilogram or a minimum dose of forty milligrams for one to three weeks, followed by a taper, is a reasonable approach.

Repeated infusion of intravenous D--H--E may be a reasonable transitional therapy for some patients, but is limited to refractory patients because it requires an infusion center or inpatient setting.

A third transitional option is to administer sphenopalatine ganglion or occipital injections of a steroid with or without an anesthetic, providing pain relief for one to two weeks.

Kingston WS, Dodick DW. Treatment of Cluster Headache. Ann Indian Acad Neurol. 2018 Apr;21(Suppl 1):S9–15.

29 Preventive drug therapies for cluster headaches, that can be started at the onset of a cycle, include primarily oral medications: verapamil, topiramate or valproate or lithium, but their use may be limited by intolerance or contraindications and ten to twenty percent of patients are not effectively treated by or become resistant to these therapies. Verapamil, used in high doses (eighty milligrams four times daily for a total daily dose of two-hundred- forty milligrams, but sometimes as high as nine-hundred-sixty milligrams daily) is perhaps the most effective long-term preventive treatment for cluster headaches. It takes several weeks to work. Topiramate is FDA-approved for migraine prevention but is also useful in cluster headache. The CGRP blocker, galcanezumab, is the first of this class of medication to earn FDA approval for the indication of acute episodic cluster headache in adults.

Psilocybin is not currently legally available but patients have found it to be effective in relieving the agonizing pain of cluster headaches. The most safe and effective formulation and dosing is now being studied.

Be aware of a number of other therapies, including hypothalamic deep brain stimulation, use of continuous positive airway pressure, or CPAP equipment, to treat the common comorbidity of obstructive sleep apnea, and zonisamide, that may be effective for select patients.

PMay A. Cluster headache: Pathogenesis, diagnosis, and management. Lancet 2005; 366: 843–855 Savoldi F, Bono G, Manzoni GC, Micieli G, Lanfranchi M, Nappi G. Lithium salts in cluster headache treatment. Cephalalgia. 1983 Aug;3 Suppl 1:79–84. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-episodic-cluster- headache-reduces-frequency-attacks

30 Harm Reduct J [Internet]. 2017 Sep 5 [cited 2019 Jun 9];14. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584001/ Gooriah R, Buture A, Ahmed F. Evidence-based treatments for cluster headache. Ther Clin Risk Manag. 2015 Nov 9;11:1687–96. Limmer AL, Holland LC, Loftus BD. Zonisamide for Cluster Headache Prophylaxis: A Case Series. Headache. 2019;59:924-929.

30 Since inhaled oxygen is a uniquely effective treatment for cluster headaches, it is important that you be familiar with how to order it for your patients. Oxygen therapy depends on a patient hyperventilating one-hundred percent oxygen at a high flow with a rebreather mask for fifteen to twenty minutes. Oxygen therapy is more effective when the user breathes more rapidly and deeply than usual, but there are different breathing techniques that are personal preferences. Limit the hyperventilation to twenty minutes to avoid excessive stress on the cardiovascular system.

One study demonstrated that this therapy, delivered at the start of a cluster attack, effectively relieved pain in almost eighty percent of subjects, in contrast to twenty percent among those who used only high-flow room air.

Oxygen therapy can also enhance the effectiveness of other rescue and preventive medicine. A mask is needed to avoid mixing the pure oxygen with air. A non-rebreather mask, which covers both the nose and mouth and has a reservoir bag attached, is preferred. The Optimask is designed specifically for people with

31 cluster headache. For home use, a large M tank is more efficient because, at a flow rate of fifteen liters per minute, it can deliver ten twenty--minute sessions. But, when traveling, it is necessary to have a smaller E tank which, at the same flow rate, can deliver less than two twenty-minute sessions. For some, a homemade backpack design is even better. For those familiar with an “oxygen concentrator”, it cannot deliver one-hundred percent oxygen. Each oxygen tank also needs a high-flow regulator appropriate for its size. A prescription should include the details describing a flow rate of twelve to fifteen liters per minute with a non-rebreather mask. Extra credit for requesting two M and two E tanks with high-flow regulators. There are possible issues regarding pre-authorization and explaining to oxygen delivery services that, unlike C--O--P--D patients, cluster patients may not need a routine delivery of new oxygen tanks.

Cohen A, Burns B, Goadsby P. High-Flow Oxygen for Treatment of Cluster Headache. JAMA. 2009;302(22):2451-2457.

31 In a large international survey of acute treatments of cluster headache patients, triptans and oxygen both achieved the highest rate of complete or very effective treatment. DHE and cafergot, caffeine and energy drinks, intranasal ketamine, opioids, intranasal capsaicin (pronounced kap-ˈsā-ə-sən), and intranasal lidocaine had modest to poor efficacy.

Oxygen has the advantage of the lowest adverse effects. Triptans, D--H--E and opioids had the highest rates of side effects.

Other studies have demonstrated higher rates of pain control in acute cluster headache attacks with 6 mg of subcutaneous sumatriptan but with an almost thirty percent rate of severe side effects. Subcutaneous sumatriptan is slightly less effective for chronic cluster headache. Even lower doses of two or three milligrams can be highly effective with less severe side effects. While patients may prefer six milligrams of subcutaneous sumatriptan to lower doses or even oxygen, it is good to offer the options for the best individualized care.

Pearson SM, Burish MJ, Shapiro et al. Effectiveness of Oxygen and Other Acute Treatments for Cluster Headache: Results from the Cluster Headache Questionnaire, an International Survey. Headache. 2019; 59:235-249.

Gregor N, Schlesiger C, Akova-Oztürk E, Kraemer C, Husstedt I-W, Evers S. Treatment of cluster headache attacks with less than 6 mg subcutaneous sumatriptan. Headache. 2005 Sep;45(8):1069–72.

Ekbom K, Krabbe A, Micelli G, et al. Cluster headache attacks treated for up to three months with subcutaneous sumatriptan (6 mg) Cephalalgia. 1995;15:230–236. [PubMed] [Google Scholar]

Göbel H, Lindner V, Heinze A, Ribbat M, Deuschl G. Acute therapy for cluster headache with

32 sumatriptan: findings of a one year long-term study. Neurology. 1998;51:908–911. [PubMed] [Google Scholar]

32 Be prepared for your cluster patients to know more about their disease than you do.

Great resources for you and your patients are the website (animate) Clusterbusters.org and authoritative new book (animate) Cluster Headaches: A Guide to Surviving One of the Most Painful Conditions Known to Man. A Cluster Headache Book for Patients, Supporters & Doctors by Ashley J. Hattle.

33 a. TRUE. b. FALSE. They usually are short, lasting only minutes and characteristically less than 3 hours c. TRUE. d. FALSE. They often occur more than once per day e. TRUE. f. TRUE. g. FALSE. 85% have periods of remission Migraine is particularly variable and disabling for women. Now why would that be...if it is not related to the insidious effect of sex hormones, particularly estradiol and its metabolites, on a vulnerable nervous system. What do we know about what is going on for women with migraine and do we, and can we, treat women with migraine differently?

35 The extraordinary effect of sex hormones on the nervous system is clear. The onset of puberty triples the prevalence of females with migraine symptoms. Migraine is estimated to affect 37% of women ages 25-55 which is, of course, during their most productive years of work and parenting. And roughly 70% of those women experience a headache during their menstrual cycle.

Edlow AG, Bartz D. Hormonal Contraceptive Options for Women With Headache: A Review of the Evidence. Rev Obstet Gynecol. 2010;3(2):55–65. MacGregor EA, Hackshaw A. Prevalence of migraine on each day of the natural menstrual cycle. Neurology. 2004 Jul 27;63(2):351–3.

36 Migraine is best understood as a syndrome expressed in several different subtypes that differ in their symptom presentation and respond to certain treatments better than others. A good example is menstrual migraine.

(Start with graphs) For this subtype of migraine, hormone levels make a big difference. With ovulation, estradiol levels peak at about 400 pg/mL (pē-kō-ˌgrams per milliliter). The subsequent drop in estradiol by more than 200 pg/mL, followed by a similar fall in progesterone, during the luteal phase trigger the menstrual headache. When in their early 30’s, 20% of females with migraine have migraine headaches associated with 50% of their menses. It is helpful to remember that a woman with menstrual migraine may not have a headache with every menstrual cycle.

There are two separate clinical variants of menstrual migraines: (Animate) those where the headache and other symptoms occur only during the 5 days of menses, called pure menstrual migraine, and (Animate) those headaches and other symptoms that occur both during the 5 days of menses and at other times, called menstrually- related migraine

Fewer than 15% of women with menstrual migraines have headaches only with menses. Most women have menstrually-related migraine. Calhoun AH. Understanding Menstrual Migraine. Headache: The Journal of Head and Face Pain. 2018 Apr 1;58(4):626–30.

Epstein MT et al. Lancet. 1975.1:543-547 Silberstein SD. Sex hormones and headache. Rev Neurol (Paris). 2000;156 Suppl 4:4S30-41.

IHS. Cephalalgia. 2004.24(suppl 1):139

37 (Animate) Pure menstrual migraine headaches typically are more intense and (animate) last longer than other forms of migraine. They are usually (animate) more likely to be a chronic form of migraine, more resistant to treatment and (animate)associated with more disability. (animate) They are not usually associated with aura.

And, for those women who suffer from menstrually-related migraine, (animate) they often have twice as many headaches during their menses and (animate) those headaches can be 2-4 times more severe than headaches during other times of the month.

Maasumi K, Tepper SJ, Kriegler JS. Menstrual Migraine and Treatment Options: Review. Headache. 2017 Feb;57(2):194–208. Spierings ELH, Padamsee A. Menstrual-Cycle and Menstruation Disorders in Episodic vs Chronic Migraine: An Exploratory Study. Pain Med. 2015 Jul;16(7):1426–32. MacGregor EA, Hackshaw A. Prevalence of migraine on each day of the natural menstrual cycle. Neurology. 2004 Jul 27;63(2):351–353.

38 (Animate) Estrogen is considered a migraine trigger. The abrupt fall of estrogen is believed to be the primary trigger of headaches when they occur during menstruation. But women experience changes in headaches during pregnancy, breastfeeding and perimenopause. These are times when fluctuating levels of estrogen appear to exacerbate headaches. Menopause brings a drop-off in estrogen production and, for two thirds of women, an end to their headaches. Of course, this does not account for those women who first experience migraine headaches when their hormones decline after menopause.

(animate) A less studied phenomenon is the rise in secondary migraine symptoms, such as vestibular migraine, balance difficulties, midfacial pressure and autonomic symptomatology, cognitive deficiencies and sleep disturbances, during the perimenopausal phase of hormone transition.

Sacco S, Ricci S, Degan D, Carolei A. Migraine in women: the role of hormones and their impact on vascular diseases. J Headache Pain. 2012 Apr;13(3):177–189.

Vacca V, Marinelli S, Pieroni L, et al. 17beta-estradiol counteracts neuropathic pain: a behavioural, immunohistochemical, and proteomic investigation on sex-related differences in mice.

Sci Rep [Internet]. 2016 Jan 8;6. Available from:

39 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705539/

How the sex hormones affect neural excitability, inflammation and vascular flow is not fully understood, but there is evidence for at least three mechanisms. (Animate) Hormones can act as neurotransmitters. Estrogen and progesterone receptors are found throughout cortical and subcortical structures in the brain. In addition to the drop in estrogen, prostaglandin plays a role in menstrual migraine.

(Animate) Secondly, hormones can act as neuromodulators. Estrogen derivatives may increase trigeminal pain sensitivity or neuroinflammation by modulating, or enhancing, the effects of other neuropeptides, such the principle pain transmitters CGRP and glutamate. Estradiol also increases neuronal sensitivity by augmenting glutamate receptor activity.

Foulkes T, Wood JN. Pain Genes. PLoS Genet [Internet]. 2008 Jul 25;4(7). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2432024/

((Animate) Estrogen is believed to be the primary hormonal trigger of menstrual migraine headaches. Rather than a specific concentration of estradiol, it is the abrupt fall of its level during the menstrual cycle that is the trigger. But mere fluctuations in estrogen levels during pregnancy, breastfeeding and perimenopause may also affect the frequency and intensity of headaches. And menopause represents a drop in estrogen production and, for two thirds of women, an end to their headaches. And to underscore the complexity of hormonal changes on the nervous system, there are women who first experience migraine headaches after menopause.

(animate) A less studied phenomenon is the rise in new migraine symptoms, such as vestibular migraine, midfacial pressure and autonomic symptomatology, cognitive deficiencies and sleep disturbances, during perimenopause. These are variants that further reinforce the concept of migraine as a syndrome and demand that we, as clinicians, need to take a more holistic view of our patient’s complaints when dealing with this heterogeneous condition.

How the sex hormones affect neural excitability, inflammation and vascular flow is not fully understood, but there is evidence for at least four mechanisms. (Animate) First, hormones, both estrogen and progesterone metabolites can act as neurotransmitters. Although the physiological details have not been worked out, estrogen and progesterone receptors are found throughout cortical and subcortical structures in the brain.

39 (Animate) Second, hormones can act as neuromodulators. Estrogen derivatives may increase trigeminal pain sensitivity or neuroinflammation by modulating...that is, either enhancing or dampening down...neuronal transmissions, using a number of different processes often within the synaptic junctions of nerve cells.

(Animate) Another process involves either estrogen receptors on cell membranes or nerve cell nuclei. By binding to cell membrane receptors, estradiol can rapidly change cell functions. This is believed to result in increased pain and neuroinflammation. Alternatively, estradiol can pass easily through cell membranes where it can bind to nuclear estrogen receptors, thereby altering gene transcription and production of neuropeptides, neurotransmitters and neuroreceptors.

For example, this slow-acting mechanism is thought to play a part in both the onset of the menstrual cycle and increased pain. To explain the increase in pain, it starts with a fall in estrogen levels. This results in a drop of serotonin, dopamine and endorphin production. And lower levels of these neurotransmitters render pain pathways more sensitive.

(Animate) A third mechanism is based on preliminary evidence suggesting that distinct susceptibility genes create women who are more vulnerable to hormone modulation. Finally, (Animate) estrogens have direct effects on the cerebral vasculature.

Littleton-Kearney MT, Agnew DM, Traystman RJ, et al. Effects of estrogen on cerebral blood flow and pial microvasculature in rabbits. Am J Physiol Heart Circ Physiol. 2000;279:H1208–14.

39 FALSE. Roughly 70% of those women experience a headache during their menstrual cycle. And women with menstrual migraine may not have a headache with every menstrual cycle. Fewer than 15% of women with menstrual migraines have headaches only with menses. FALSE. Estradiol and its derivatives an affect the production of neurotransmitters and can act neurotransmitters and neuromodulators. TRUE. FALSE. The estrogen membrane receptors initiate rapid changes in cell metabolism, unlike the estrogen nuclear receptors which are slow acting because they must work through transcription of genetic material to produce new proteins. TRUE. In caring for young adult women who complain of headaches, an important clinical step is to (animate) ask them about the relationship of the headaches and other symptoms to their menstrual cycle. If your patient is not sure how to answer this question, you might suggest that she start a (animate) headache diary. By tracking the timing and severity of symptoms, (animate) this information will help to individualize your treatment plan.

41 To treat a menstrual migraine, a patient can use the same familiar interventional, or “on-demand”, medications. However, menstrual migraine symptoms respond more poorly to these medicines and the FDA has not approved any therapies specifically for this use.

Here are reasonable guidelines for choosing among the available options.

For mild to moderate symptoms, patients can choose from the following analgesics: ibuprofen, naproxen or an acetaminophen-aspirin combination with or without caffeine.

For moderate-severe symptoms, the recommendation is to use an oral triptan - with or without a nonsteroidal. For acute treatment, frovatriptan has the best overall evidence because it provides longer lasting pain relief. Because of the high prevalence of nausea during menstrually related migraine, an antiemetic, such as metoclopramide, is strongly recommended. When these interventional medicines are ineffective, the next choices are 4 or 6 mg of subcutaneous sumatriptan, 30 or 60 mg of intramuscular ketorolac, or a nasal spray 0.5 mg of DHE in each nostril - this can be repeated in 15 minutes.

Broner S, Bobker S, Klebanoff L. Migraine in Women. Seminars in Neurology. 2017 Dec;37(06):601–10.

42 Maasumi K, Tepper SJ, Kriegler JS. Menstrual Migraine and Treatment Options: Review. Headache. 2017 Feb;57(2):194–208.

42 (animate) For those who have failed to control their menstrual headaches and nausea with interventional, or “rescue”, medications, it is appropriate to use the preventive strategies that we studied in module 2, including (animate entire list) non- medicinal approaches to calm and control the nervous system.

43 And because menstrual migraine symptoms are related to hormonal changes, trying a non-pharmaceutical supplement may be an appealing option.

(start with all but the last line visible) Phytoestrogens are naturally occurring plant compounds that are structurally and/or functionally similar to mammalian estrogens and their active metabolites.

(Animate last line) Current evidence that they help to control any menopausal symptoms is weak at best, with most clinical trials showing no or minimal relief. One feature that stands out in nearly all studies is a large placebo effect which is obviously a desirable effect.

Looking specifically at menstrual or menopausal migraines, there are virtually no studies of phytoestrogens that conclude that they are effective preventive agents.

http://lpi.oregonstate.edu/mic/dietary-factors/phytochemicals/soy-isoflavones

Patisaul HB, Jefferson W. The pros and cons of phytoestrogens. Front Neuroendocrinol. 2010 Oct;31(4):400–19. Cassidy A, Albertazzi P, Lise Nielsen I, Hall W, Williamson G, Tetens I, Atkins S, Cross H, Manios Y, Wolk A, Steiner C, Branca F. Critical review of health effects of soyabean phyto-oestrogens in post- menopausal women. Proc. Nutr. Soc. 2006;65:76–92.

Sirtori CR, Arnoldi A, Johnson SK. Phytoestrogens: end of a tale? Ann Med. 2005;37:423–438.

Chen M, Lin C, Liu C. Efficacy of phytoestrogens for menopausal symptoms: a meta-analysis and systematic review. Climacteric. 2015 Mar 4;18(2):260–9.

Treatment of menopause-associated vasomotor symptoms: position statement of The North American Menopause Society. Menopause. 2004;11:11–33.

Burke BE, Olson RD, Cusack BJ. Randomized, controlled trial of phytoestrogen in the prophylactic treatment of menstrual migraine. Biomedicine & Pharmacotherapy. 2002 Aug 1;56(6):283–8.

44 Unlike other types of migraine that occur more randomly, menstrual migraines have a more predictable pattern. Therefore, one can consider (animate) a preventive strategy where agents are used only in the “menstrual” window, the week beginning at the onset of their bleeding to its completion.

(animate) An example of this is would be to increase the dose of a traditional preventive medicine in anticipation of one’s period.

(animate) Let’s consider this strategy if your patient were taking an antiepileptic medication.

Recall anti-epileptics are not favored for women of childbearing age who are using oral contraceptives because they can cause enzyme induction, which, in turn, decreases oral contraceptive effectiveness. They can also reduce the effectiveness of hormonal replacement therapy - a subject that we will discuss soon.

Nonetheless, there are still many women who rely on (animate) topiramate to control their headaches and this anti-epileptic, at a dose below 200 mg/day, is the best choice of this class of popular preventive medication because it undercuts the efficacy of birth control pills to a lesser degree.

45 Therefore, there are some women suffering from menstrual migraines and are on a low dose of topiramate might prefer to increase topiramate by (animate) 25 to 50 mg during the anticipated vulnerable portion of a patient’s cycle. Maasumi K, Tepper SJ, Kriegler JS. Menstrual Migraine and Treatment Options: Review. Headache. 2017 Feb;57(2):194–208.

45 The strategy where preventive medications are used only for the week before menstruation in anticipation of a menstrual migraine headache is called (animate) mini-prophylaxis.

(animate “options” with first bullet point) They include the use of supplements, (animate) nonsteroidal anti-inflammatory agents, or (animate) triptans.

The major drawback of mini-prophylaxis is that to be effective, a woman must have a regular and predictable menstrual cycle, and most women have variable lengths of time between their periods.

Nonetheless, let’s review each strategy.

46 For those who prefer supplements, magnesium may play a particularly essential role in menstrual migraines and (animate) a daily dose of 400 mg started on the 14th day of the cycle for a week is safe and might be effective.

Facchinetti F, Sances G, Borella P, Genazzani AR, Nappi G. Magnesium prophylaxis of menstrual migraine: effects on intracellular magnesium. Headache. 1991 May;31(5):298–301.

Mauskop A, Altura BT, Altura BM. Serum ionized magnesium in serum ionized calcium/ionized magnesium ratios in women with menstrual migraine. Headache. 2001;42:242–248.

47 Most women use nonsteroidal anti-inflammatory drugs for pain relief, but it can also be used as a preventive agent. (animate) An example would be to start a long-acting nonsteroidal agent, such as naproxen 500 mg twice a day, several days before the anticipated onset of the migraine and (animate) continue through the third day of the cycle. While a 5-day regimen of naproxen may only slightly reduce the number of headaches, it is likely to reduce the intensity of the pain.

(Animate) Celecoxib is another alternative. Nonsteroidal agents are a safe and cost-effective choice for prevention of menstrual migraine.

Allais G, Bussone G, De Lorenzo C, Castagnoli Gabellari I, Zonca M, Mana O, et al. Naproxen sodium in short-term prophylaxis of pure menstrual migraine: pathophysiological and clinical considerations. Neurol Sci. 2007 May;28 Suppl 2:S225-228.

48 (Animate) A short course of a triptan twice daily, beginning several days before the anticipated onset of migraine is another method to prevent menstrual migraines.

(Animate) The longer acting triptans, frovatriptan and zolmitriptan, are preferred.

Preventive triptans can be used in (Animate) combination with traditional prophylactic agents. Despite mini-prophylaxis, 40% of women still have some pain and must use (Animate) nonsteroidal agents to control the pain.

The bottomline is that all mini-prophylactic strategies are limited in their effectiveness primarily because women have to have predictable menstrual cycles and headaches. Other drawbacks occur when there are breakthrough headaches. (Animate) A patient should not mix different types of triptans and (Animate) this strategy exhausts a patient’s monthly supply of triptans. Additionally, this use of triptans is (Animate) not FDA approved and theoretically (Animate) might have damaging consequences for the nervous system. Sullivan E, Bushnell C. Management of Menstrual Migraine: A Review of Current Abortive and Prophylactic Therapies. Curr Pain Headache Rep. 2010 Oct;14(5):376– 84.

49 Silberstein SD, Elkind AH, Schreiber C, Keywood C. A randomized trial of frovatriptan for the intermittent prevention of menstrual migraine. Neurology, 2004. 63:261-269.

49 A. FALSE. Triptans are not the first line drug for a menstrually related headache. Acetaminophen is. But triptans are effective second-line “on-demand” pain relievers. The long-acting triptan frovatriptan has the best overall evidence of efficacy. B. FALSE. Mini-prophylaxis with triptans may be a strategy that is used only for an occasional select patient because 40% of your patients will breakthrough these longer-acting triptans, they preclude the use of the most effective interventional medication - triptans. Also, the use of triptans continuously for a week may risk nerve injury. C. TRUE. D. TRUE. E. TRUE. ((start with the graph visible)

Menstrual migraines have been attributed to falling estrogen and progesterone levels at the onset of menstruation.

It is during the luteal phase of the menstrual cycle - those 10-14 days before one’s period - when estradiol drops more than 200 units from its peak at about 400 pg/mL and precipitate menstrually related headaches - (animate “Prevention strategy and Stabilize…”) Therefore, one strategy for migraine prevention is to stabilize estradiol concentration to less than 20 micrograms within each menstrual cycle with exogenous estrogen.

Since drops in progesterone are also associated with increases in headaches, (animate) stabilizing levels of progesterone with supplemental exogenous progesterone also can prevent menstrually related migraine headaches.

Calhoun AH, Hutchinson S. Hormonal therapies for menstrual migraine. Curr Pain Headache Rep.2009;13(5):381-385.

51 It is tempting to think that smoothing out the fluctuations of endogenous hormones with supplemental exogenous ones would avoid menstrually related migraine headaches. Unfortunately this strategy is complicated. First issue is one of vascular complications. To start, anyone who has migraine carries an increased risk factor for ischemic stroke. That is a vascular phenomenon that starves a portion of the brain of adequate blood flow and oxygen and accounts for 80% of all types of stroke. There are many possible explanations for why migraine causes ischemic stroke. However, for reasons unknown, this risk of stroke is even higher in women who have migraine with aura.

For comparison, the lifetime risk of an ischemic stroke of women aged 20-50 is 7.5 per 100,000 women. At age 20, for women without migraine the risk for women without migraine is small, 2 of every 100,000 people, but that risk of ischemic stroke increases with age. At age 40, 11 women of every 100,000 may experience a stroke.

If we add the additional risk factor of having migraines, (animate) the number of 20 year old females with migraine having a stroke rises mildly to 8 of every 100,000. At age 50 (animate) the average number of women with migraine that experience a stroke has risen to 70 of 100,000. While a history of migraine may be the only

52 significant risk factor for stroke in women younger than age 35 years, hypertension and other traditional metabolic risk factors at this age.

Finally, the bar on the far right represents the average number of women at age 50 and take any of the commonly available combined oral contraceptives who might develop a stroke: 200 per 100,000.

Edlow AG, Bartz D. Hormonal Contraceptive Options for Women With Headache: A Review of the Evidence. Rev Obstet Gynecol. 2010;3(2):55–65.

Scher AI, Launer LJ. Migraine with aura increases the risk of stroke. Nat Rev Neurol. 2010 Mar;6(3):128–9.

52 There are four factors that contribute to the risk of an ischemic stroke among women with migraine. First, (animate) those who have auras with their migraine attacks account for the doubling of the risk of stroke over those without migraine. It is speculated that during an aura, blood vessels constrict and therefore this form of migraine has a different effect on the body’s vasculature. The second factor is (animate) the effect of birth control pills. The problem is that the supplemental estrogen in combined makes blood more “sticky” and raises the risk of clotting and subsequently ischemic stroke. For women without migraine who take an oral contraceptive, the relative risk of stroke is minimal at 1.4, but for women with migraine without aura who take the pill, this relative risk increases slightly to 2.2, but it is those migrainous women with auras, taking the pill for whom the risk jumps to a relative risk of 6.1 where the threat becomes a significant health risk. This is a similar risk with a vaginal ring or patch formulation. Women with aura who seek birth control should consider an alternative method, such as an intrauterine device. The third factor is (animate) smoking tobacco. Women under 35 who smokes can use an oral contraceptive with reasonably low risk of stroke, but when a woman reaches the age of 35 and smokes, especially more than 15 cigarettes daily, her risk of a stroke rises to a more significant level. For women desiring birth control, she may also want to avoid common estrogen supplements. One study found that smoking, not

53 the presence of auras, that accounted for the increased risk of stroke among older women with migraine. Monteith TS, Gardner H, Rundek T, et al. Migraine and risk of stroke in older adults: Northern Manhattan Study. Neurology.2015;85(8):715-721. The final major risk factor is to have (animate) additional cardiovascular conditions.

53 The cardiovascular risk factors that increase the risk of an ischemic stroke are (animate each bullet point separately –hypertension, diabetes, hyperlipidemia, clotting disorders, obesity, previous history of cardiovascular disease, previous history of deep vein thrombosis or pulmonary embolism. For a woman with migraine and cardiovascular risk factor, this is an opportunity to advise and support her to make lifestyle changes, such as stopping smoking, losing weight, healthy eating and exercise.

54 Before we alarm all of our female patients, it is worth noting that (animate) the absolute risk of ischemic stroke is low in women of reproductive age. Afterall, a third of all women seek birth control at any point in their lives and a third of those women will have some form of migraine. With so many women who fall into this demographic, it is critical to understand that the risk of hormone supplementation has been lowered over time. A 1996 World Health Organization study contained an early general warning that combined oral contraceptives increased the risk of heart disease, emboli and strokes. (animate) At the time of that study (animate) combined oral contraceptives contained more than 50 micrograms of estradiol. Since then all birth control pills containing 50 micrograms or more of estradiol have been removed from the market.

Over time it has become apparent that lower doses of exogenous estrogen reduce the risk of ischemic stroke and embolic clots without a significant loss of protection from pregnancy.

(Animate) In 2017 a study of 85,000 U.S. women found that (animate) hormone formulations that contained less than 30 micrograms of estradiol did not carry a significant risk of heart attack or stroke, even if they had a history of migraine headaches.

55 Today, the use of oral combined contraception is still limited by concerns about stroke, particularly in those 20% of women who have migraine with aura. And concerns remain about women, regardless of the presence of aura or not, who have cardiovascular risk factors and as they grow older. In summary, the absolute risk of stroke for combined estrogen-progesterone contraceptives with low levels of estrogen is very low for many women with migraine, but the American College of Obstetricians and Gynecologists and the World Health Organization hold the position that the use of combined estrogen-progesterone contraception, especially in oral, vaginal or patch formulations, (animate) should be avoided for a woman with migraine headache (animate) if she is 35 years of age or older, (animate) has migraine with aura, (animate) smokes tobacco or (animate) has any cardiovascular risk factors. Ischaemic stroke and combined oral contraceptives: results of an international, multicentre, case-control study, authors. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet. 1996;348:498–505.

Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002 Jul 17;288(3):321–33. Schwartz SM, Petitti DB, Siscovick DS, et al. Stroke and use of low-dose oral contraceptives in young women: a pooled analysis of two US studies. Stroke. 1998;29:2277–2284.

U.S. Medical Eligibility Criteria for Contraceptive Use, 2010 [Internet]. [cited 2018 Jul 15]. Available from: https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5904a1.htm Curtis KM. U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR Recomm Rep [Internet]. 2016 [cited 2018 Jul 15];65. Available from: https://www.cdc.gov/mmwr/volumes/65/rr/rr6503a1.htm Women’s Health Initiative (WHI) presented at The North American Menopause Society (NAMS) Annual Meeting, 2017.

Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002 Jul 17;288(3):321–33.

55 In fact, many women with menstrual or menstrually related migraines, who fail conventional migraine preventive therapies, may be able to use hormone contraceptives to reduce the burden of migraine. Recall that there are two general categories of contraceptives: (animate) those with a combination of estrogen and progesterone and (animate) those with only progesterone. (animate) Also, recall that combined oral contraceptives are traditionally packaged with 21 pills containing supplementary estrogen and progestin and then 7 pills without any active ingredient, often called placebo, designed to allow menstrual bleeding. There are three forms of estrogen: estrone, estriol (the most potent) and estradiol (the most commonly prescribed estrogen). Finally, there are two common forms of estrogen in birth control pills: conjugated equine estrogen and bio-identical estrogen.

(animate - start with Estrogens and the first line only) Conjugated equine estrogen is synthetized from horses and has been commonly used in birth control pills. Side effects of these synthesized estrogens include breast tenderness and enlargement, headache, fluid retention, and nausea among others. It may increase the risk of endometrial hyperplasia and endometrial cancer in women with an intact uterus if it is not taken together with a progestogen. Most importantly, synthesized estrogen may cause more headaches than (animate second line) bio-identical

56 estrogen. Bioidentical estradiols, which better match natural hormones, are associated with fewer serious complications.

56 The second hormone in combined birth control pills is progesterone. Artificial versions of the progesterone, (animate) progestins, have evolved through 4 generations of birth control pills. (animate) Coupled with high doses of estradiol, the first generation progestins were linked to some health scares and are no longer manufactured. (animate) The next generations of pills came into use in the 1970s, and had a much lower amount of hormones and fewer androgenic properties. (animate- add both 3rd and 4th generation text together) Now combined oral contraceptives contain third or fourth generation progestins which are better tolerated, but do have an increased risk of venous blood clots and pulmonary emboli. The second generation progestin levonorgestrel has the lowest risk of venous clotting. But the advantage of third and fourth generation progestins are that they do not carry the risk of increased ischemic strokes.

57 Today combination oral contraceptives (animate) contain estradiol levels varying from 20 to 50 micrograms per pill. The lower doses of estrogen (animate) do lower the risk of stroke while still effectively protecting against pregnancy. Unfortunately, while there are approximately 30 traditional formulations of combined oral contraceptives, almost all commercially available products contain the seven days of placebo pills. This birth control with placebo is (animate) not an ideal preventive formulation for any woman with migraine because, during the seven days of placebo, estrogen drops more than 20 micrograms and can, therefore, causes (animate) an increase in migraine auras and headaches. There is no evidence that shortening the number of placebo days reduces this risk. Clinical evidence, albeit limited, also suggests that oral contraceptive with placebo use in young women with episodic migraine (animate) may transform their pattern into chronic migraine.

Since hormones may not be consistently absorbed from the gastrointestinal system, not to mention that contraceptives may cause nausea, (animate) dosing is an imperfect science.

Finally, this form of contraception offers (animate) no protection against ovarian

58 cancer. Susan Hutchinson, M.D., director of the Orange County Migraine & Headache Center in Irvine, California

Brandes JL. Migraine in women. Continuum (Minneap Minn). 2012 Aug;18(4):835–52.

58 (Animate) The better strategy for treating women with menstrual migraine without aura is continuous oral contraception, or extended cycle estrogen. Any series of pills containing the same dose of progesterone and estradiol at a dose of less than 35 microgram can be used continuously without placebos.

Continuous combined oral contraceptives have been shown (animate) to reduce headache severity, (animate) menstrual bleeding and (animate) the risk of ovarian cancer by 50%.

(Animate) Since it is recommended to cycle off estradiol every 3-6 months, consider utilizing a short-term preventive strategy of a transdermal 0.1 mg estradiol patch the week of placebo. Estradiol patches do not contain progesterone which allows menstrual bleeding to occur.

(Animate) There are a few commercially available pill packs that may be appropriate for menstrual migraine prevention. The first FDA-approved extended release oral contraceptive contained 30 micrograms of ethinyl estradiol and levonorgestrel. The pack contained 12 weeks of active pills followed by 1 week of placebo. A variation of this pill pack is one that substitutes 10 micrograms of estradiol for the last week

59 instead of placebo.

(Animate) As with traditional formulations of combined oral contraceptives, the continuous formulations should still be avoided in women with aura because their estrogen content still carry risks of blood clots, stroke and more auras.

Vetvik KG, MacGregor EA, Lundqvist C, et al. Contraceptive-induced amenorrhoea leads to reduced migraine frequency in women with menstrual migraine without aura. J Headache Pain.2014;15:30 Sulak P, Willis S, Kuel T, et al. Headaches and oral contraceptives: impact of eliminating the standard 7-day placebo interval. Headache. 2007;47:27-37.

59 Non-oral delivery systems, such as estradiol gel, contraceptive rings or transdermal patches may offer safer options for women with menstrual migraine because when they are not absorbed through the gut, they may minimize the first pass through the liver which avoids increases in clotting factors.

(Animate) Although not commonly used, estradiol 1.5 mg gel can be administered once daily for 7 days during the menstrual period. This more subtle modification of the menstrual cycle can be modestly effective in reducing menstrual migraine.

Patients should be informed that delayed migraine may occur and that treatment is potentially only effective for attacks related to menstruation. Estradiol gel can be used with or without oral contraceptives. (Animate) The vaginal contraceptive ring, like birth control pills, contains estradiol and progesterone that are absorbed through the vaginal lining. It stops ovulation and needs to be replaced once a month.

Use of low dose vaginal rings can reduce the number of headaches in women who have migraine with aura.

The preferred recommendation is to use an (Animate) estradiol patch 0.1 mg. It has

60 benefits similar to the gel study. It is convenient and provides a more steady level of hormone.

The patch currently on the US market contains 35 micrograms estradiol with progesterone. Transdermal delivery results in fewer peaks and troughs of estrogen, but a higher total estrogen exposure compared with combined contraceptive pills. Though studies show mixed results, the risk of developing venous thromboembolism may be twice as high with the patch as with the oral formulation; however, the absolute risk of venous thromboembolism remains low.

Patches with lower levels of estrogen are ineffective. Apply the patch 3 days before menses and remove when menses is complete - usually no more than 6 days. There are other strategies, such as 3 weeks of an estradiol patch followed by one week without supplementation, but this is not as effective as extended regimens of the patch.

Estrogen-Progestin injections, once a month, are an effective, but less popular, alternative. Nappi RE, Merki-Feld GS, Terreno E, Pellegrinelli A, Viana M. Hormonal contraception in women with migraine: is progestogen-only contraception a better choice? J Headache Pain. 2013;14(1):66. de Lignieres B, Vincens M, Mauvais-Jarvis P, et al. Prevention of menstrual migraine by percutaneous oestradiol. Br Med J (Clin Res Ed). 1986;293:1540.

Sacco S, Merki-Feld GS, Ægidius KL, Bitzer J, et al. Effect of exogenous estrogens and progestogens on the course of migraine during reproductive age: a consensus statement by the European Headache Federation (EHF) and the European Society of Contraception and Reproductive Health (ESCRH). J Headache Pain. 2018 Aug 31;19(1):76. Pradalier A, Vincent D, Beaulieu PH, et al. Correlation between oestradiol plasma level and therapeutic effect on menstrual migraine. In Rose FC, ed. New Advances in Headache Research. 4th ed. London: Smith-Gordon;1994:129-132.

Galzote RM, Rafie S, Teal R, Mody SK. Transdermal delivery of combined hormonal contraception: a review of the current literature. Int J Womens Health. 2017 May 15;9:315–21. Calhoun AH. Understanding Menstrual Migraine. Headache: The Journal of Head and Face Pain. 2018 Apr 1;58(4):626–30.

60 60 The safest hormone strategy to prevent menstrual migraine is to use (animate “advantages” and “prevent headaches....”) continuous progestin-only contraception. By stabilizing the drop in progesterone during the menstrual cycle, the progestin-only pill, containing desogestrel 75 micrograms, reduces the number of days with migraine, the number of analgesics and the intensity of associated symptoms for the majority of women with and without aura. Progestin-only contraception has the major advantage of (animate) not affecting the coagulability of blood and therefore avoids the increased risk and may even reduce the risk of venous clots and stroke. It can be used in circumstances where estrogen is contraindicated and it may be an option for (animate) breastfeeding women and (animate) older women, but with caution. This option is particularly important (animate) for women that have migraine with aura, because progesterone-only contraceptives are safe for use in these women, even in the presence of other risk factors for stroke.

Progesterone-only contraceptives are available as a (animate) progestin-only pill, (animate) injection, (animate) implant, or (animate) intrauterine device.

61 Progestin intrauterine devices do not protect against headaches as well as other formulations.

The progestin works as a contraceptive by thickening the cervical mucus, making it difficult for sperm to go through the cervix and enter the uterus. It also makes the endometrium thinner, making it difficult for a fertilized egg to implant. Newer pills, containing third generation progestogens act principally by preventing the release of the egg from the ovary. These progestin-only forms of contraception were previously classified as category B risk. That means that there is no evidence of risk in humans if a woman does become pregnant, but also there are no controlled studies.

But women need to know that supplemental progestin (animate) carries a slightly higher risk of pregnancy, (animate) may stop normal menstrual bleeding and may be associated with unscheduled menstrual bleeding. A progestin-containing implant which needs to be replaced only every 5 years, often causes menstrual bleeding to become significantly lighter and shorter and, for 20 percent of women, it will disappear all together.

Also, (animate) about 12 percent of women to grow one or more ovarian cysts, which normally go away on their own, but, in rare cases, they can cause pain or require surgery.

While progestin-only contraception appears to be the safest and most effective hormone treatment for women who fail conventional migraine treatment, even if they have auras, it is important to emphasize that more prospective trials need to be performed to confirm that progestin-only oral contraception is a safer and more effective management of both migraine and birth control. Nappi RE, Merki-Feld GS, Terreno E, Pellegrinelli A, Viana M. Hormonal contraception in women with migraine: is progestogen-only contraception a better choice? J Headache Pain. 2013;14(1):66.

61 In a situation where you are caring for a patient who is asking for a form of contraception or if your patient who has migraine symptoms that are not responding to conventional therapies, there are a few basic pieces of information on which to formulate a plan.

(animate) Screen for the presence of migraine (animate) Identify the subtype (with or without aura). (animate) Remember the risks of stroke increases after age 35 (animate) Smoking, especially more than 15 cigarettes a day, is a contraindication for some forms of birth control (animate) Check for the presence of vascular risk factors, specifically, (animate) (Lisa - the pauses can be relatively short because people hopefully have become familiar to these risk factors) high blood pressure, (animate) diabetes, (animate) hyperlipidemia, (animate) previous history of cardiovascular disease, deep vein thrombosis or pulmonary embolism, or (animate) obesity.

62 Creating an accurate set of guidelines for medical professionals is currently difficult because rigorous scientific study of alternative formulations is lacking. But let’s look at the 2018 consensus statement from the European Headache Federation and the European Society of Contraception and Reproductive Health.

(Animate) Continuous combined hormonal contraceptives, with pill, patch, transdermal gel or vaginal ring, is suggested for women with menstrual-related migraine who require migraine preventive treatments and who have a contraindication or failure of conventional medical treatment or have estrogen withdrawal headaches. With a broader indication (Animate) the progestin-only “mini pill” is potentially the most useful form of contraception because it is indicated for women with migraine, related or unrelated to menstruation, who might have health risks, estrogen withdrawal headache or worsening of the usual headache with combined hormonal contraceptives.

Sacco S, Merki-Feld GS, Ægidius KL, et al. Effect of exogenous estrogens and progestogens on the course of migraine during reproductive age: a consensus statement by the European Headache Federation (EHF) and the European Society of Contraception and Reproductive Health (ESCRH). J Headache Pain. 2018 Aug 31;19(1):76.

63 To determine the eligibility for a woman for a contraceptive under various medical conditions, please refer to the guidelines developed by (animate) the American College of Obstetricians and Gynecologists and (animate) those adopted the Centers for Disease Control and Prevention. They are available online, free of charge.

ACOG Practice Bulletin No. 206: Use of Hormonal Contraception in Women With Coexisting Medical Conditions. Obstetrics & Gynecology. 2019 Feb;133(2):e128. Centers for Disease Control and Prevention. US Medical Eligibility Criteria for contraceptive use. MMWR, 2016;65:3

64 A. FALSE. The week of placebo pills does not protect women from migraine symptoms. Conventional 21/7 contraception also offers no protection against ovarian cancer. B. FALSE. Any formulation of birth control pills that contain estrogen may carry a risk of blood clotting and stroke. Currently we understand that oral contraceptives are more safe when they contain ≤35 μg ethinylestradiol. C. TRUE. D. TRUE. E. FALSE. Progestin-only pills can be used in women with and without aura. It is the safest contraceptive preventive strategy for most women. Pregnancy also changes the pattern of migraine symptoms. Estrogen rises dramatically – as high as one hundred times its normal level, while progesterone levels decrease until the end of the pregnancy. (Animate) During the first 3 months or more of pregnancy, headaches often worsen. It may be the first sign of pregnancy. Thankfully, these symptoms usually improve about halfway through pregnancy. (Animate) During the second half of pregnancy, estradiol levels stabilize and the majority of women have a reduction or complete remission of migraine symptoms. But for 30-40% of women, migraine symptoms remain unchanged throughout their pregnancy. More rarely, a few women have worse headaches or the first onset of migraine symptoms during their pregnancy, perhaps related to dehydration, lack of sleep and stress.

(Animate) For most women this temporary relief from headaches can end within days of delivery. Again exhaustion, dehydration, erratic sleep and low blood sugar may all play a part, but it is the severe drop in estrogen after delivery that is likely the most significant factor.

66 One warning about headaches during pregnancy. While migraine headaches tend to improve during the course of pregnancy, there is an increase in the prevalence of secondary headaches. This is because any woman with migraine has a higher risk of gestational hypertension, pre-eclampsia, eclampsia, ischemic stroke and thromboembolic events. In the general public less than 10% of headaches are secondary to another underlying cause, but during pregnancy, 35% are secondary headaches and many of these represent potential serious complications. In other words, when a pregnant woman has a new or worsening headache, do not assume that it is just another migraine headache.

The most common secondary headache during pregnancy is pre-eclampsia. This is often a generalized throbbing headache with nausea and light sensitivity. It may occur in up to 8% of all pregnancies. It presents near the end of pregnancy, usually after 20 weeks of gestation. To distinguish this secondary headache from migraine, check for hypertension and protein in the urine. Eclampsia is the same problem with hypertension but complicated by seizure.

And, while a third of women have a recurrence of their migraine headache after delivery as estrogen levels drop, many women develop new secondary headaches after their pregnancy and need a thorough evaluation also.

O’Neal MA. Headaches complicating pregnancy and the postpartum period. Pract Neurol. 2017 Jun;17(3):191–202.

67 Vgontzas A, Robbins MS. A Hospital Based Retrospective Study of Acute Postpartum Headache. Headache. 2018 Jun;58(6):845–51.

Sances G, Granella F, Nappi RE, Fignon A, Ghiotto N, Polatti F, et al. Course of migraine during pregnancy and postpartum: a prospective study. Cephalalgia. 2003 Apr;23(3):197–205.

Bushman ET, Varner MW, Digre KB. Headaches Through a Woman’s Life. Obstetrical & Gynecological Survey. 2018 Mar;73(3):161.

67 Let’s turn our attention to treating migraine headaches in a pregnant woman. The safest treatments include (Animate) nerve blocks, (Animate) neuromodulators, (Animate), complementary medical therapies and (Animate) micronutrients, also known as nutraceuticals.

Among the micronutrients,(Animate) magnesium and riboflavin at doses of 400 mg daily are considered to be safe. Other options are melatonin, and ginger. Some nutraceuticals can be risky, (Animate) such as feverfew, Coenzyme Q10 and 5-HTP and some essential oils – for example, rosemary - and should be avoided until more is known about their effects on the fetus. With that current warning, it is worth noting that coenzyme Q10 supplementation during pregnancy did reduce pre-eclampsia and theoretically could be helpful during the oxidative stress periods of pregnancy.

(Animate) Applying heat or cold can reduce the pain.

(Animate) Some women do well with 200 mg of caffeine daily to prevent headaches, which is roughly equivalent to 12 cups of coffee, but there is the risk of headache when the caffeine wears off.

(Animate) Massage, acupuncture, cognitive behavioral therapy, biofeedback and

68 other disciplines can be helpful and safe. Encourage patients to maintain moderate exercise, keep to routines, get plenty of rest and ask for help.

(Animate) You may want to recommend a lighter work schedule.

These measures may be sufficient to get your patient through the first trimester. Measures that are effective should be continued, even when breastfeeding.

Teran E, Hernandez I, Nieto B, Tavara R, Ocampo JE, Calle A. Coenzyme Q10 supplementation during pregnancy reduces the risk of pre-eclampsia. Int J Gynaecol Obstet. 2009 Apr;105(1):43–5.

68 For those women who find the nonprescription treatments insufficient, both interventional and preventive drugs for migraine are used. The choice must foremost include the effect on the baby. The decision to use medications is complicated by not being able to perform studies on pregnant women, for obvious ethical reasons. Therefore, we have to rely on reports of birth defects or pregnancy complications, including bleeding, miscarriage and intrauterine growth restriction.

Interventional treatment of an acute migraine attack is usually limited to nonprescription pain relievers. Of these, (Animate) acetaminophen is probably the safest, but even this medicine should be limited during pregnancy. (animate) Nonsteroidal pain medicines are considered reasonably safe if used in early pregnancy. But, after 30 weeks, nonsteroidal agents must be avoided because of the increased risk of premature closure of the fetal ductus arteriosus and reduced volumes of amniotic fluid.

(Animate) Anti-nausea medicines appear to be safe and are often needed during pregnancy. Although there has been warning of birth defects if antiemetics are used during the first trimester, a large study did not find a risk any higher than those who did not use an antiemetic.

69 Also, (Animate) triptans are relatively safe to use during pregnancy, based on the triptan registry and 25 years of clinical experience.

(Animate) On the other hand, avoid all aspirin products, which increase the risk of bleeding and are associated with miscarriages and possible Reye's (pronounced “rise”) syndrome in the neonate.

(Animate) Ergotamines are contraindicated because of potential vascular and uterine constriction.

(Animate) There are currently no good prescription drug regimens for migraine prevention during pregnancy.

(Animate) Low-dose amitriptyline, specifically below 50 mg daily, is sometimes prescribed; however, there are reports of limb deformities following prenatal exposure to higher doses.

(Animate) Beta-blockers may increase the risk of intrauterine growth retardation. The highest risk is with atenolol at 25%.

(Animate) Topiramate and sodium valproate should be avoided because of the risk of oral clefts. OnabotulinumtoxinA is not currently indicated for migraine prevention during pregnancy but that might change as clinical experience has suggested that exposure to botulinum toxin does not appear to increase the risk of complications to the fetus.

With the introduction and promise of CGRP blockers, we will have to see if there are complications to the fetus reported to the FDA. Currently medical professionals should inquire if their female patients of reproductive age are on birth control. If there is any plan to try for pregnancy, this form of migraine prevention, which might block important developmental functions of CGRP, should be stopped 4 months before coming off birth control.

Cannabinoids are increasingly used during pregnancy because they are considered by the public to be a safer option for controlling pain and nausea. Until we have more information, it is important to explore alternative therapies with our pregnant patients because cannabinoids are associated with lower weight births and cognitive developmental complications. “Lasting Impacts of Prenatal Cannabis Exposure and the Role of Endogenous

69 Cannabinoids in the Developing Brain.” Accessed July 21, 2019. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3252200/.

Li D-K, Liu L, Odouli R. Exposure to non-steroidal anti-inflammatory drugs during pregnancy and risk of miscarriage: population based cohort study. BMJ. 2003 Aug 16;327(7411):368.

Pasternak B, Svanström H, Mølgaard-Nielsen D, Melbye M, Hviid A. Metoclopramide in pregnancy and risk of major congenital malformations and fetal death. JAMA. 2013 Oct 16;310(15):1601–11.

Duong S, Bozzo P, Nordeng H, Einarson A. Safety of triptans for migraine headaches during pregnancy and breastfeeding. Can Fam Physician. 2010 Jun;56(6):537–9. "Product Information. Botox (onabotulinumtoxin A)." Allergan Inc, Irvine, CA. Tan M, Kim E, Koren G, Bozzo P. Botulinum toxin type A in pregnancy. Can Fam Physician. 2013 Nov;59(11):1183–4.

69 A 2018 report on pregnant women with migraine who presented to the emergency department revealed that intractable headaches were an increasingly severe problem with the progression of the pregnancy: (animate) only 10% were in their first trimester, (animate) about 40% were in their second trimester and (animate) 50% were in their third trimester. A third of them had not tried any acute medication and almost 50% of them had had a headache for more than 3 days.

The most common medications prescribed were (animate) metoclopramide, usually with diphenhydramine, and (animate) acetaminophen. Other interventions were an (animate) intravenous fluid bolus, (animate) butalbital, (animate) opioids, (animate) intravenous magnesium and (animate) nerve block.

We are now familiar with safe choices, such as triptans and nerve blocks, that should be first line choices in this setting. Avoid barbiturates, such as butalbital, and opiates due to the fetal risk of bleeding or birth defect.

Hamilton KT, Robbins MS. Migraine Treatment in Pregnant Women Presenting to Acute Care: A Retrospective Observational Study. Headache. 2019;59:173-179.

For pregnant women with cluster headaches, oxygen therapy is the first line abortive treatment. The alternative is a triptan. Nasal spray formulation is

70 preferred because of lower serum concentration. Only verapamil and corticosteroids are possible preventive medications. Peripheral nerve blocks may be another choice.

Asioli GM, Merli E, Favoni C, et al. Greater Occipital Nerve Infiltration During Pregnancy in Cluster Headache: A Case Report. Headache. 2019;59:930-932.

In closing, women with migraine have greater risk of several adverse pregnancy outcomes. These include hypertension disorders, miscarriage, low birth weight, preterm birth, cesarean delivery and other risks to the newborn.

Skajaa N, Szepligeti SK, Xue F, et al. Pregnancy, Birth, Neonatal, and Postnatal NeurologicaL Outcomes After Pregnancy with Migraine. Headache. 2019;59:869-879.

70 S - rizatriptan (triptan) - relatively safe R - amitriptyline (tricyclic antidepressant) - limb deformity S - onabotulinumA toxin - relatively safe R - naproxen (NSAID) - contraindicated in the third trimester - increased risks of miscarriage, malformations, premature closure of the fetal ductus arteriosus and reduced volumes of amniotic fluid volume R - topiramate (antiepileptic) - risk of the birth defect of a cleft lip R - butalbital (barbiturate) - fetal risk of bleeding or birth defect R - galcanezumab (CGRP monoclonal antibody) - unknown, needs to be reported to FDA if unexpected pregnancy during administration S - metoclopramide (antiemetic medication) - no significant risks R - aspirin- possible Reye's syndrome/bleeding and miscarriage R - propranolol (beta-blocker) - intrauterine growth retardation Whether or not headaches resolve during breastfeeding (animate) is variable. For some, more stable estrogen levels during lactation protect against headache. (animate) But a third of women who had migraine attacks before pregnancy experience a recurrence of those attacks during the first week after childbirth; (animate) and more than 50% do during the first month. For those women who experience migraine headaches, (animate) we want to facilitate breastfeeding so we may need to recommend temporary changes in treatment. Although all drugs can pass through the breast milk to the baby, (animate) breast milk is generally protective for a child. Breast milk typically contains only 1 to 2 percent of the dose that the baby would have received in-utero. The calculation of infant exposure has several variables including the volume of ingested milk, the baby’s absorption of the drug and infant age. (animate) At highest risk are newborns, premature infants and infants with acute or chronic medical conditions that affect the processing of medications. (animate) Infants at moderate risk are term infants who are 2 weeks to 6 months in age. (animate) Infants at low risk are generally older, between 6-18 months, because, by six months of age, babies can metabolize and excrete drugs as well as adults, relative to their body size.

But the most useful and accurate measure of exposure is to calculate (animate) the relative infant dose, or RID. (lisa, say R-I-D) The RID is generally expressed as a

72 percentage of the mother’s dose. A rough rule of thumb is an RID greater than 10% may be a level of concern for drug toxicity. Sances G, Granella F, Nappi RE, Fignon A, Ghiotto N, Polatti F, et al. Course of migraine during pregnancy and postpartum: a prospective study. Cephalalgia. 2003 Apr;23(3):197–205.

Rowe H, Baker T, Hale T. Maternal Medication, Drug Use, and Breastfeeding. Child Adolesc Psychiatric Clin N Am.24 (2015) 1-20.

72 (animate) In a September 2013 clinical report, “The Transfer of Drugs and Therapeutics Into Human Breast Milk: An Update on Selected Topics,” the American Academy of Pediatrics (AAP) provides guidance to physicians regarding drug exposure and reaffirms the recommendation that most medications are safe during lactation.

Another resource is a manual entitled Medications and Mothers Milk written by Thomas Hale, PhD. The author reviews scientific literature and assigns (animate: Hale Lactation Rating L1-L5) a lactation risk category (or LRC) to all listed medications. It is available as a paperback book and can be ordered online at iBreastfeeding.com. A third resource is the (animate) National Library of Medicine's Drugs and Lactation database. It is free and available for both providers and patients. A recent addition is a free downloadable app. This database is updated every 1–2 months. LactMed does not assign any rating system to medication for lactation; it simply lists all that is known about a particular medication in regard to lactation. A fourth comprehensive reference examining the safety of medication in both pregnancy and lactation is (animate) Drugs in Pregnancy and Lactation by Briggs, Freeman, and Yaffe. The authors provide recommendations for breast-feeding based in large part on human data, such as milk and maternal plasma levels, infant drug levels after exposure, and reported adverse events. Their categories for breast-

73 feeding recommendations are listed in Table 2.

For more detailed information, please read the PDF on this subject. (can use tables from Hutchinson article) http://toxnet.nlm.nih.gov.13

Hutchinson S, Marmura MJ, Calhoun A, et al. Use of Common Migraine Treatments in Breast-Feeding Women: A Summary of Recommendations. Headache: The Journal of Head and Face Pain. 2013 Apr 1;53(4):614–27.

73 While many medications are considered to be compatible with breastfeeding, studies on breastfeeding women and their infants have rarely been performed. Most of the same recommendations and warnings about migraine medications during pregnancy apply to breastfeeding.

Let’s look at our routine choices for interventional medications.

Among the most safe on-demand pain relievers, there are (Animate) acetaminophen, (animate) ibuprofen, (animate) naproxen and (animate) triptans. Here is an example of the difference between RID and Hale Lactation rating. Acetaminophen passes more readily into breast milk than naproxen, but it has fewer side effects and therefore has a more favorable Hale Lactation rating. On the other hand, triptans are rated as a third level choice, but anecdotally triptans are considered safe for a baby because triptan concentrations in breast milk as very low.

Other alternative interventional migraine medicines are the (Animate) antiemetics,(Animate) caffeine and (Animate) nerve blocks. Among the antiemetics, dimenhydrinate, ondansetron, and metoclopramide are considered among the safest choices, while prochlorperazine is not recommended. Ginger may be a safer alternative for nausea.

74 A related issue is when women are not able to produce adequate breast milk. Milk production may be increased with the use of a dopamine antagonist, which stimulates the release of prolactin. Metoclopramide, 10-15 mg 3 times daily, is the most commonly used and effective strategy and may offer a secondary gain for women with migraine.

(Animate) Cannabinoids are generally considered safe for adults, but they concentrate in breast milk. There is significant absorption in infants, although the dose received is apparently insufficient to produce significant side effects. It is still unclear if there will be long-term risks on growth, mental and motor development when cannabinoids are ingested as a newborn.

(Animate) The pain medicines that need to be avoided are aspirin in high doses, ergots, barbiturates (such as found in Fioricet) and opioids - with the possible exception of meperidine Duong S, Bozzo P, Nordeng H, Einarson A. Safety of triptans for migraine headaches during pregnancy and breastfeeding. Can Fam Physician. 2010;56(6):537–539. Weibert RT, Townsend RJ, Kaiser DG, et al. Lack of ibuprofen secretion into human milk. Clin Pharm 1982;1(5):457–8. Bitzen PO, Gustafsson B, Jostell KG, et al. Excretion of paracetamol in human breast milk. Eur J Clin Pharmacol 1981;20(2):123–5. Jamali F, Stevens DR. Naproxen excretion in milk and its uptake by the infant. Drug Intell Clin Pharm 1983;17(12):910–1. . Rowe H, Baker T, Hale T. Maternal Medication, Drug Use, and Breastfeeding. Child Adolesc Psychiatric Clin N Am 24 (2015) 1-20. Nezvalova-Henriksens K, et al. Triptan Exposure During Pregancy and the Risk of Major Congenital Malformations and Adverse Pregancy Outcomes. Headache. 2010.

74 The safest strategies for prevention of migraine during breastfeeding are (animate) the micronutrients magnesium and riboflavin. (Animate with Antidepressants) Tricyclic antidepressants, such as amitriptyline, (animate) serotonin norepinephrine reuptake inhibitors, such as venlafaxine, and (Animate) serotonin reuptake inhibitors, such as sertraline, are all considered low risk preventive agents during breastfeeding. Of special note, recent data indicate that postpartum depression affects 12-20% of women. The use of antidepressants during lactation is widely accepted as safe. Selective serotonin reuptake inhibitors are presently the mainstay of antidepressant therapy because of low transfer into breast milk. Unfortunately, sertraline, which is overwhelmingly favored for postpartum depression, and other SSRIs are not effective preventive agents for migraine.

(Animate with Antihypertensives) Antihypertensives are also considered to be of low risk to the baby. Among the antihypertensive medications, propranolol and verapamil have the safest known profiles.

(Animate with Anti-seizure medications) Anti-seizure medications are also probably compatible with breastfeeding. Although the transfer of topiramate into human milk is significant, it is considered a safe preventive medication during breastfeeding

75 because infant plasma levels are low and no adverse effects have been reported.

(Animate) Some patients may want to try alternative nonmedicinal therapies, including acupuncture, biofeedback, and neuromodulators. Finally, the FDA has concluded that the benefits of onabotulinumtoxinA injections during breastfeeding outweigh the risks, but it remains unknown if the botulinum toxin is excreted into human milk.

Rowe H, Baker T, Hale T. Maternal Medication, Drug Use, and Breastfeeding. Child Adolesc Psychiatric Clin N Am 24 (2015) 1-20. Landy S, McGinnis J, Curlin D, Laizure SC. Selective serotonin reuptake inhibitors for migraine prophylaxis. Headache. 1999 Jan;39(1):28–32. Ohman I, Vitols S, Luef G, et al. Topiramate kinetics during delivery, lactation, and in the neonate: preliminary observations. Epilepsia 2002;43(10):1157–60. "Product Information. Botox (onabotulinumtoxin A)." Allergan Inc, Irvine, CA.

75 General Considerations to share with Breastfeeding Mothers: (Animate) When possible, choose a medication that will expose the baby to the least amount of the medication. (Animate) Avoid long-acting forms of medications. This could be important in the case of topiramate. (Animate) Try taking medication at time of or immediately following breastfeeding. (Animate) Watch the baby for unusual signs and symptoms, such as sleepiness, irritability, or other potential or known effects of the medication.

76 riboflavin (nutraceutical) - SAFE sumatriptan (triptan) - SAFE verapamil (anti-hypertensive) - SAFE venlafaxine (SNRI) - SAFE codeine (opioid) - CONTRAINDICATED acetaminophen - SAFE butalbital (barbiturate) - CONTRAINDICATED amitriptyline (tricyclic antidepressant) - SAFE ibuprofen (NSAID) - SAFE high doses of aspirin - CONTRAINDICATED onabotulinumA toxin - SAFE metoclopramide (anti-emetic) - SAFE magnesium (nutraceutical) - SAFE topiramate (anti-epileptic) - SAFE And then there is the onset of menopause. This dramatically variable hormonal environment has a complex effect on migraine disease. As a standardized staging system and research tool for reproductive aging, the revised Staging System for Reproductive Aging in Women, or ReSTRAW, divides the transition from perimenopause to postmenopause into 10 phases.

For our purposes the onset of menopause, or perimenopause, can be divided into two symptomatic phases: the early and late phases. (animate) The early phase is when estrogen and progesterone first drop to low levels and amenorrhea starts but there are still surges of sex hormones. The early phase of perimenopause is associated with (animate) wide fluctuations in estrogen and progesterone and cause (animate) high frequency headaches and (animate) worsening of menstrual migraines.

(animate) The late phase is (animate) when drops in estrogen do not rebound and menstrual bleeding stops for longer periods of time. It can be associated with (animate) even worse pain, depression and anxiety. This late phase increases the use of pain relievers and raises the risk of medication overuse headaches.

When women start to miss their periods during the late phase of perimenopause, women are still experiencing hormonal cycling. (Animate) Taking supplemental

78 estrogen can help regulate the cycling and migraine symptoms.

In the early menopausal phase when women with menstrual migraines are either having more frequent periods or their periods are very heavy, (Animate) there are two possible treatments using supplemental estrogens.

(Animate) One option is low dose oral estradiol, starting 3 days before menses. Unpredictable perimenopausal menstruation makes timing this dosing largely impractical.

The second is to use a (animate) low-dose estradiol patch, at a level well below 0.1 mg per 24 hours. This level of estradiol is a balance between a dose that is less effective in controlling headaches and one that minimizes the risk of ischemic stroke. Of course, transdermal delivery of estradiol, rather than oral, carries less risk of stroke.

(animate) You and your patient may want to discuss this with a gynecologist or menopause specialist. Harlow SD, Gass M, Hall JE, Lobo R, Maki P, Rebar RW, et al. Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging. Menopause. 2012 Apr;19(4):387–95. Martin VT, Pavlovic J, Fanning KM, Buse DC, Reed ML, Lipton RB. Perimenopause and Menopause Are Associated With High Frequency Headache in Women With Migraine: Results of the American Migraine Prevalence and Prevention Study. Headache: The Journal of Head and Face Pain. 2016 Feb 1;56(2):292–305..

Martin VT, Pavlovic J, Fanning KM, Buse DC, Reed ML, Lipton RB. Perimenopause and Menopause Are Associated With High Frequency Headache in Women With Migraine: Results of the American Migraine Prevalence and Prevention Study. Headache: The Journal of Head and Face Pain. 2016;56(2):292–305.

78 The next phase of hormonal change is menopause. It is defined by 12 months without a period. The average age of woman in menopause is 51 years. 90% of women reach menopause by age 55. Although early studies report that migraine symptoms often diminished or resolved with menopause, more recent ones show a variety of patterns including changes, plateauing, increased symptoms and even the onset of migraine symptoms. (animate) Overall, two thirds of women experience a reduction in headaches during menopause. (animate) One estimate is that the percentage of women over 60 years of age experiencing migraine headaches is 6%. (animate) After menopause, the outcomes continue to vary while the majority have symptomatic relief from headaches, but this is a topic worthy of more study because of conflicting data.

(animate) Another observation is that two thirds of women with removal of their ovaries, or a surgical menopause, had a worsening of their headaches, in contrast to the majority who experienced improved symptoms after menopause.

79 In the early menopausal phase when women are either having more frequent periods or their periods are very heavy, continuous oral contraceptives, low dose estradiol or estradiol patches are still options.

Sacco S, Ricci S, Degan D, Carolei A. Migraine in women: the role of hormones and their impact on vascular diseases. J Headache Pain. 2012 Apr;13(3):177–89. Gold EB. The Timing of the Age at Which Natural Menopause Occurs. Obstet Gynecol Clin North Am. 2011 Sep;38(3):425–40.

79 In 2002, results reported from a large U.S. government study called the Women's Health Initiative raised the alarm that combined hormonal contraceptives carry a small, but significant vascular risk for postmenopausal women with migraine.

But, once a woman no longer ovulates, the amount of hormone needed to suppress egg production is no longer needed for birth control. At this stage in life, a strategy called hormone replacement therapy, often abbreviated to HRT, uses lower doses of hormones than with birth control pills. The standard dose of HRT delivers one quarter of the estrogen of a 20 microgram contraceptive. HRT typically raises estrogen levels to physiological levels seen during the reproductive years. HRT can be used during perimenopause, menopause and postmenopause.

In the United States, the most commonly used hormonal replacement therapy uses (Animate) conjugated equine estrogens. They are usually taken (Animate) by mouth or applied topically as a skin patch, gel, cream or spray.

While HRT is associated with significantly fewer complications than contraceptive levels of hormones, conjugated equine estrogens and “synthesized” estrogens can be limited by their (Animate) side effects. They include (Animate) breast tenderness and enlargement, headache, fluid retention and nausea. For women who have not had

80 their uterus removed, progesterone or progestin is added. This is because estrogen alone, when not balanced by progesterone, (Animate) can stimulate growth of the lining of the uterus which increases the risk of uterine cancer. Combined estrogen and progestin pills increase serious risks include (Animate) blood clots and cardiovascular disease. A transdermal estrogen patch reduces the risk of clotting and venous thrombosis, compared with oral therapy. This is particularly a better option for women with obesity or cardiovascular disease risk factors.

Conjugated equine and synthesized estrogens are being replaced by low dose bioidentical estradiol which is (Animate) associated with fewer serious complications, particularly fewer headaches.

Many women request bioidentical, or natural, hormones because of a perception of increased safety. Women should be informed that bioidentical is a marketing term. The term bioidentical hormone refers to exogenous hormone products that are chemically similar to endogenous hormones. Compounding personalized doses of bioidentical hormones should be discouraged due to variable potency and purity. There is no acceptable evidence that bioidentical hormones are more effective or safer than conjugated or fully synthetic hormones.

(animate: Indications) These estrogens are approved for control of (animate) postmenopausal hot flashes, vulvovaginal atrophy and for various other indications.

(animate) This can include women with postmenopausal migraine symptoms who have failed other traditional therapies and have no contraindications.

Unfortunately, HRT does not offer a predictable migraine treatment. Some women with migraine get great relief while others feel worse. HRT may trigger migraine attacks in women without a history of migraine or a reappearance of migraine in women who had this disorder before menopause. Non-oral routes of delivery of estrogen are more likely to improve migraine than oral, probably because of lower fluctuations in estrogen levels.

To date, no specific preventive HRT is recommended for menopausal women with migraine.

But the current consensus for postmenopausal women with difficult-to-treat migraine symptoms is to use an estrogen patch.

80 With many challenging issues surrounding HRT, consulting a menopause specialist is recommended. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002 Jul 17;288(3):321–33.

Broner S, Bobker S, Klebanoff L. Migraine in Women. Seminars in Neurology. 2017 Dec;37(06):601–10.

Shifren JL, Crandall CJ, Manson JE. Menopausal Hormone Therapy. JAMA. 2019;321(24):2458-2459.

MacGregor EA. Is HRT giving you a headache? Br Migraine Assoc Newsletter. 1993:19-24 Ripa P, Ornello R, Degan D, Tiseo C, Stewart J, Pistoia F, et al. Migraine in menopausal women: a systematic review. Int J Womens Health. 2015 Aug 20;7:773– 82. Sacco S, Ricci S, Degan D, Carolei A. Migraine in women: the role of hormones and their impact on vascular diseases. J Headache Pain. 2012 Apr;13(3):177–89.

Misakian AL, Langer RD, Bensenor IM, Cook NR, Manson JE, Buring JE, et al. Postmenopausal hormone therapy and migraine headache. J Womens Health (Larchmt). 2003

80 So, if hormone replacement therapy uses lower doses of estrogen than oral contraceptives, are the risks of stroke and other cardiovascular events reduced?

Studies and recommendations are still conflicting. (Animate) In 2017 the US Preventive Services Task Force, a government-backed panel of experts, renewed its recommendation that “postmenopausal women should not use hormone therapy to prevent chronic medical conditions, because the risk of significant side effects outweighs the unclear evidence of a benefit.”

(animate) But, in a separate study, hormone replacement therapy with conjugated equine estrogens plus medroxyprogesterone acetate was (animate) not associated with an increased risk of cardiovascular or cancer mortality.

(animate) To date, hormone replacement therapy regimen to control and prevent headache remains controversial. published online in the Journal of the American Medical Association.

Manson JE, Aragaki AK, Rossouw JE, et al. Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women’s Health Initiative Randomized Trials. JAMA.2017;318(10):927-938.

Misakian AL, Langer RD, Bensenor IM, Cook NR, Manson JE, Buring JE, et al.

81 Postmenopausal hormone therapy and migraine headache. J Womens Health (Larchmt). 2003 Dec;12(10):1027–36.

81 Menstrual and transitional menopause migraine symptoms can be managed effectively using a variety of strategies, the choice of which depends on the efficacy of acute treatment, predictability and regularity of menstruation, use of contraception, and presence of menstrual disorders or perimenopausal vasomotor symptoms. In conclusion, this is a topic without clear treatment guidelines. If your patient is not doing well with traditional migraine medications and you believe that your patient would benefit from either a specialized formulation of birth control pills or hormone replacement therapy, it is usually best to consult and work with an expert in women’s health. Also, women need to learn about these issues and advocate for better care. Recommended resources books, such as Not Tonight: Migraine and the Politics of Gender and Health by Joanna Kempner, PhD or Migraines: A Self- Help Guide to Feeling Better, by Wendy Green. See online list of 11 Books That Shine a Light on Migraines. https://www.healthline.com/health/migraine/books-shine-light-migraines#1 MacGregor EA. Migraine management during menstruation and menopause. Continuum. 2015;21:990-1003. Toward Optimized Practice. (Primary Care Management of Headache in

82 Adults, 2nd Edition) http://www.topalbertadoctors.org/download/597/Guideline%20for%20Primary% 20Care%20Management%20of%20Headache%20in%20Adults.pdf?_2017021 523 4414. Accessed February 18, 2017.

82 True or False

Estrogens may affect the genetic expression of migraine disease by binding to nuclear receptors. True.

Current low dose hormonal replacement therapy carry minimal cardiovascular and stroke risks. True.

The early phase of perimenopausal is associated with the worst migraine symptoms and comorbidities. False. It is the late phase when estrogen is fluctuating and dropping that women generally experience the worst symptoms.

Until more study, acetaminophen, ibuprofen and triptans are the most safe interventional medicines to use while breastfeeding. False. It is acetaminophen, metoclopramide and triptans that are considered the most safe interventional medicine to use while breastfeeding. 84 As this course in migraine management concludes, it is worth remembering how important this complex neurological condition is to our patients, their families, their friends and our economy.

(animate) In the World Health Organization’s 2013 Global Burden of Disease Study, headache disorders were found to be the third highest cause worldwide of “years lost due to disability”.

People with this disease may miss work but the majority do go to work but cannot function at full capacity.

(animate) EMPLOYERS lose $14.5 BILLION every year to lost productivity (animate) Annual cost of an employee with migraine is about $5000.

(animate) And the annual average cost for a worker with episodic migraine is $1,757 and (animate) for a worker with chronic migraine: $7,750

85 There are also (animate) costs in quality of life, particularly the stress on social relationships, especially family members.

Linde M, Gustavsson A, Stovner L, et al.The Cost of headache disorders in Europe: The Eurolight Project. Eur J Neurol. 2012; 19: 703–711

85 As you develop your skills in migraine management and may need an occasional consultation for a more complicated patient, please check this resource for a headache specialist or headache center near you.

(animate) For a comprehensive listing of all of the major organizations that contribute to migraine patient care, information and advocacy, the Coalition for Headache and Migraine Patient website provides one-stop shopping.

86 If you want to let people know about your particular interest in migraine care, the Association of Migraine Disorders provides a listing of medical professionals who welcome new patients. This is a site designed for those who have not obtained advanced training and certification to become a “headache specialist”.

87 For those who would like to continue their education in migraine disease and receive a certification that credits your expertise, there are two options.

The National Headache Foundation Certificate of Added Qualification, or CAQ, in Headache Medicine Examination. Its cost is, for NHF members, $600 ($300 for nurse practitioners and physician assistants) and, for non-members, $800 ($500 for NPs and PAs). For more information, see the link https://headaches.org/caq/

The certification needs to be renewed every 5 years.

Headache Medicine examination administered through the United Council for Neurologic Specialities (UCNS). This certification examination has more demanding qualification requirements including 12 months of formal training.

https://americanheadachesociety.org/tool-kit-for-ucns-headache-board- certification/ https://www.ucns.org/globals/axon/assets/11907.pdf

88 89 90 91