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Histamine is best known as a part of the defense against allergies. But it is also an important neurotransmitter – a brain chemical involved in arousal, anxiety, the stress-related release of hormones, activation of the sympathetic nervous system, pain relief, and other functions.

Increased sensitivity to histamine may lead to an excessive allergic reaction which is relieved by anti-histamine drugs. It can also increase pain. One strategy thought to reduce this over-reaction is desensitization – injecting small amounts of histamine which can lead to a reduced reaction.

This approach seems to help some migraine and cluster patients. It was first reported in 1941 by a Mayo clinic doctor, Bayard Horton in an article entitled The use of histamine in the treatment of specific types of headaches. Another article, Intravenous histamine in the treatment of migraine was published in 1946 by W.A. Thomas and S. Butler.

A group of Mexican doctors compared subcutaneous (under the skin) injections of small doses of histamine to injections of placebo in 60 patients. They found histamine to be more effective. The same group of doctors conducted three more double-blind trials of histamine injections. A double-blind study of 90 migraine patients compared twice-weekly injections of histamine with 100 mg of oral topiramate, which is an FDA-approved treatment for migraines. These treatments were equally effective. They then compared twice-weekly injections of histamine to 500 mg of valproate, which is also an FDA-approved migraine drug in 92 migraine patients. Histamine was superior to valproate. They compared histamine to the injection of a relatively small dose of Botox (50 units, while the standard dose is155 units) in 100 patients and found them to be equally effective.

These results would be more convincing if another group confirmed these findings. When I asked the opinion of an allergy specialist in NYC, Dr. Michael Chandler he told me that the idea of histamine desensitization has been discredited and that it is not being used to treat allergies.

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Acetyl-leucine (Tanganil) is an amino acid that has been available in France for over 60 years as a prescription drug. It is approved for the treatment of low blood pressure and dizziness. However, there are no published studies of this product for either low blood pressure or dizziness. There are some animal studies suggesting that acetyl-leucine works on brain cells responsible for the balancing of the body and motor control. It was also tested in animals whose inner ear balancing organ was destroyed on one side.

A group of German doctors, whom I know and respect, found it to be very effective in a prospective study of 10 patients with migraines. The dose was 5 grams daily. The usual recommended dose for dizziness and hypotension is up to 2 grams.

I occasionally recommend it to desperate patients with severe and persistent dizziness and vertigo that has resulted from a concussion or vestibular migraine.

While acetyl-leucine is not proven to be effective, it does not cause any side effects.

Acetyl-leucine is also being tested for some rare hereditary neurological disorders such as Niemann-Pick disease.

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Rizatriptan (Maxalt, Maxalt MLT) is one of the seven triptans approved in the US. Along with zolmitriptan, it is one of the two triptans available in an orally disintegrating form – it melts in your mouth and does not require water to take it. This is important for those migraine sufferers who are so nauseous that they cannot drink even a small amount of fluid without throwing it up. It also means that you can take it when water is not immediately available. This is important since the earlier you take an abortive drug the better the results.

Another unique feature of rizatriptan is that the FDA-approved dose is up to three 10-mg tablets a day (it is also available in 5-mg tablets), while all other triptans have a limit of 2 a day. This does not mean that there is any significant difference in how different short-acting triptans are processed in your body or that taking sumatriptan three times in one day is dangerous. Unfortunately, many doctors blindly follow the rules and sternly warn patients not to exceed the FDA-recommended dose. The 5 most effective triptans (this excludes naratriptan and especially frovatriptan) have a half-life of 2-3 hours, which means that half of a single dose is gone from your body in 2-3 hours and after 6-8 hours, almost all of it is washed out. Naratriptan has a half-life of 6 hours and frovatriptan, 26 hours. Even if you were to take narartriptan three times a day it would not endanger your life, unless you have coronary artery disease or another contraindication to triptans in general.

These contraindications include uncontrolled hypertension, history of a stroke or a heart attack, and multiple risk factors for coronary artery disease. You may still be able to take triptans if you have some risk factors, but you would need to have your coronary arteries checked with coronary calcium scoring, stress test, or an angiogram.

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Two patients treated at MD Anderson Cancer Center for brain tumors were given Botox injections for their tumor-related headaches. The report at the recent meeting of the American Headache Society describes two patients, one with a meningioma (“extensive meningiomatosis”) and the second one with metastatic breast cancer. The first patient completed 14 treatments with Botox over 4 years and the second, 9 treatments over 2 years. Both patients had sustained improvement in their headache intensity, duration, headache-free days, and quality of life. The recurrence of headaches often began 90 days after each treatment, which is the usual duration of the effect of Botox.

Botox is approved by the FDA for the preventive treatment of chronic migraine headaches, which are defined as headaches occurring on at least 15 days each month. However, most headache specialists I know use it for other types of headaches as well. Cluster headaches, hemicrania continua, post-traumatic headaches, numular headaches, trigeminal neuralgia have all been reported in the medical literature to respond to Botox. I’ve also successfully treated patients with these types of headaches, as well as a large number with episodic migraines (less than 15 headache days a month) and a few with chronic tension-type headaches.

Neuropathic pain also seems to respond to Botox and I’ve treated patients with post-herpetic neuralgia (shingles), stump pain after amputation, post-surgical scar pain, and other pain types.

It is not surprising that Botox could help headaches caused by a brain tumor. The brain itself is not pain-sensitive – neurosurgeons can cut it in an awake patient without causing any pain. Most of the pain originates in the brain covering called meninges which are innervated by the trigeminal nerve and which can be stretched and irritated by a tumor. The trigeminal nerve also provides sensation over the face and the anterior part of the head. Botox works by reducing pain signals sent from the trigeminal nerve endings to the brain.

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A large population-based 11-year long study just published by Norwegian researchers confirmed that an elevated level of an inflammatory marker C-reactive protein (CRP) is associated with an increased risk of developing chronic migraine.

Inflammation is a well-established part of the pathophysiology of migraine. Pro-inflammatory aspects of obesity are thought to underly the correlation between excessive weight and the frequency of migraines. While it is not clear how high CRP leads to chronification of migraines, there are several ways to lower this marker.

CRP is also a well-documented marker of risk for cardiovascular disease. Statins, such as atorvastatin (Lipitor) lower CRP levels independently of their lipid-lowering effect. Metformin is another drug that can lower CRP levels.

There are several ways to lower CRP without drugs including lifestyle changes such as regular exercise, a healthy diet, and moderate alcohol consumption.

A Japanese study of over 2,000 people showed that blood levels of vitamin C are inversely correlated with CRP levels. A review of 12 published studies of the effect of vitamin C on CRP showed that vitamin C lowers CRP levels.

A meta-analysis of 12 published studies showed that vitamin E (alpha-tocopherol or gamma-tocopherol) is another vitamin that lowers CRP levels.

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We recently started using RightEye eye-tracking equipment which can help our patients who are suffering from visual difficulties due to migraines, concussion, or traumatic brain injury (TBI). Many brain disorders can impair the control of eye movements. This can lead to incorrect information being passed from the eyes to the brain, which can worsen brain dysfunction. Eye strain can also contribute to migraines and post-concussion headaches.

The RightEye computer has a built-in infrared eye-tracking device that can accurately diagnose different abnormal eye movements. It tests smooth pursuit, vertical and horizontal saccades, reading, reaction time, and other functions. A recent study, Vertical smooth pursuit as a diagnostic marker of traumatic brain injury showed a correlation between moderate and severe TBI and abnormal eye movements.

Eye movement problems after TBI were also reported in a study published in the Journal of Neurotrauma , Eye Tracking Detects Disconjugate Eye Movements Associated with Structural Traumatic Brain Injury and Concussion.

A study in the journal Brain showed that eye movement difficulties were still present 3 to 5 months after the concussion and that they were not affected by the presence of depression or degree of intellectual ability. Compared with neuropsychological tests, eye movements were more likely to be markedly impaired in patients with many postconcussion symptoms.

While there are no studies showing that migraines improve with eye exercises, there is some evidence that symptoms of concussion which can include migraine headaches, do improve. A review of several published studies of vision therapy for post-concussion symptoms found it “promising”.

Why would we offer this eye movement therapy in the absence of definitive proof of its efficacy? Mostly because there are limited options for the treatment of concussion and migraines with prominent visual symptoms. We also consulted experts at SUNY College of Optometry in NYC and they were very positive about the potential benefits of this therapy.

The testing process takes about 10 minutes. If problems are found, patients are prescribed specific eye exercises that are done daily by logging into RightEye company’s portal.

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Tonight at 6 PM (EST), Dr. Mauskop will speak at the Weekly Wellness with the American Migraine Foundation. He will discuss the role of exercise in the management of migraine headaches and the results of scientific clinical trials, as well as practical information about various types of exercise such as aerobic (cardiovascular), isometric, high-intensity interval testing, and the Feldenkrais method. He will also provide advice on how to avoid exercise-induced and exertional headaches. You can log in to see this event and ask questions here – https://www.facebook.com/events/730534437480323/

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Lasmiditan (Rayvow) is the first (and probably the last) drug in the class of ditans. Just like the triptans (sumatriptan or Imitrex and other), it works through the serotonin system. However, it activates 5-HT1F serotonin receptor, while triptans activate 5-HT1B and 5-HT1D receptors. This confers an advantage in that lasmiditan does not cause constriction of coronary arteries, which can happen with triptans . So patients with a history of a heart attack, angina or multiple risk factors for vascular disease who could not take triptans, now have another drug that is safe to use. The first acute migraine drug for this at-risk population, ubrogepant (Ubrelvy) became available a week ago. Lasmiditan will reach pharmacies in the next few days.

I will also prescribe lasmiditan to patients for whom triptans and ubrogepant are ineffective, partially effective, or cause side effects, which constitutes a sizable minority of my patients. .

Results of two large double-blind trials showed that 28-39% of patients achieved fast and complete elimination of migraine pain at two hours with lasmiditan as compared to 15% and 21% with placebo. 41-49% of patients achieved freedom from their most bothersome symptom of sensitivity to light, sensitivity to sound, or nausea at two hours with lasmiditan compared to 30% and 33% with placebo.

Lasmiditan is available in 50 mg and 100 mg tablets and the recommended dose is 50, 100, or 200 mg taken once a day.

Side effects were generally mild to moderate and the most frequent ones included dizziness, fatigue, tingling, drowsiness, nausea, and muscle weakness. Two driving studies showed that lasmiditan may cause significant driving impairment.

Lasmiditan is a non-narcotic medication, has low abuse potential and no evidence of physical dependence. It is a controlled substance but is in category 5, which indicates the lowest level of potential risk of abuse.

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Clopidogrel (Plavix) was not on my original list of 100 migraine drugs, but I decided to add it after another mention of this drug at the last congress of the International Headache Society in Dublin (since I keep adding drugs and new ones are being released, the list will exceed 100).

Patients who suffer from migraines, especially those who have auras, have a higher incidence of a persistent opening between the left and the right side of their heart, called patent foramen ovale or PFO. PFO is found in 25% of the general population, is usually small and causes no symptoms. When it is large, it needs to be closed, which can be done through a vein in the groin. Unfortunately, studies that aimed to relieve migraines by closing the PFO did not show much benefit. However, blood thinners used after the procedure may have helped some patients.

I first mentioned clopidogrel in a blog post from 2007 when describing a British doctor’s experience with a few of his patients. In another blog post from 2015 I mentioned a study that showed that clopidogrel with aspirin was more effective in improving migraines than aspirin alone. A study comparing aspirin and clopidogrel showed them to be equally effective in improving migraines in patients with a PFO.

In the study presented in Dublin by two Chinese doctors PFO was found in 151 out of 266 (57%) of all migraine patients, of whom 65 the opening was large. PFO was found in 59 out of 84 (70%) of all migraine with aura and 36 patients had a large opening. 27 migraine patients who did not respond to standard medical therapy were given clopidogrel, 75 mg a day for 3 months. 22 patients completed this study. Headache frequency, severity and duration were significantly decreased by addition of this drug. Migraine-related disability was also reduced.

Aspirin, clopidogrel as well as prasugrel (Effient) and ticagrelor (Brilinta) are drugs that inhibit the function of platelets, small blood particles that are involved in blood clotting. Platelet dysfunction and other blood clotting problems have been suspected to play a role in triggering migraines, but the scientific evidence has been lacking.

A report by a cardiologist Dr. Robert Sommer and his colleagues at the Columbia University Medical Center suggests that platelets do contribute to migraines in some patients. They reviewed records of their 136 patients (86% female, mean age 38 years, with an average of 15 headache days a month). Migraines improved on clopidogrel in 80 (59%). The clopidogrel was equally beneficial in patients with episodic and chronic migraines, with and without aura. When the researchers tested platelets in non-responders, 19 of 45 (40%) did not have their platelets inhibited by clopidogrel. Sixteen of those patients were switched to prasugrel, which adequately inhibited platelets and 10 of 16 (62%) had improvement in their migraines. 56 of 90 responders had their PFO closed and the drug stopped after 3 months, which is typically done after a PFO closure. Ninety-four percent had ongoing migraine relief. All 8 of 8 responders who stopped their medication without PFO closure had worsening of their migraines.

This was not a blinded study, so it is premature to recommend PFO closure to migraine patients. However, it can be argued that patients whose migraines do not respond to several drugs, Botox, and monoclonal antibodies should have an echocardiogram to look for a PFO and if one is found, at least given a trial of an antiplatelet medication.

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Cove, a telemedicine startup provides medical care to people suffering from migraines. There are 40 million migraine sufferers in the US, only half of whom seek medical care. The other half may have mild migraines, not have access to medical care, or are under the impression that nothing can be done about their headaches. Only half of the half that go to a doctor receive a correct diagnosis of migraine. The other half, or about 10 million, are misdiagnosed as sinus, tension, or stress headaches and never receive effective treatment.

Withcove.com is website where migraine sufferers can have a neurologist evaluate their symptoms and provide an accurate diagnosis and prescribe individualized treatment. It may seem that not seeing a doctor in person would be a major obstacle, but it is not. The patient completes a questionnaire and video is used for neurological examination. The doctor evaluates the information and prescribes migraine drugs, both for the acute treatment of an attack, as well for prevention. You don’t even need to go to a pharmacy – the medicine is shipped to you. Cove also offers a variety of supplements, such as magnesium and CoQ10, which can be more effective and safer for the prevention of migraines than drugs.

My colleague at the NY Headache Center, Dr. Sara Crystal and I are helping Cove with the design of proper evaluation tools, treatment algorithms, and other aspects of care.

In addition to providing direct care, Cove is conducting some research as well. In a survey of nearly 1,000 people, a combination of Cove customers and other migraine sufferers, Cove looked at the impact of migraine on careers, to identify coping strategies, and to provide tools that make it easier to get ahead. You can read the full report, “When Migraine Gets In the Way of Careers”.

Here is a sample of the survey findings:
47% of migraine sufferers who are employed feel that migraines have held them back from advancing in their career.
30% of employed migraine sufferers said that they’ve needed to quit a job, turn down responsibilities at their current job, and/or not accept a new job because of their migraines.
38% of employed migraine sufferers have missed 5+ days of work in the past 12 months due to their migraines.

These are shocking numbers, but in line with the data known to headache specialists. Migraine is ranked globally as the seventh most disabling disease among all diseases and is the leading cause of disability among all neurological disorders. Unfortunately, research into migraines does not receive appropriate attention from the National Institutes of Health and other funding sources.

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Medication overuse headache (MOH) is not proven to occur from the frequent intake of triptans (Imitrex, or sumatriptan and other) or NSAIDs (ibuprofen, naproxen, and other). However, there is good evidence that caffeine (and opioid analgesics) which can help relieve an occasional migraine, can definitely make them worse if taken frequently. Caffeine withdrawal is a proven trigger of headaches, including migraines.

While we know that caffeine withdrawal causes headaches, a study just published by Harvard researchers in The American Journal of Medicine addressed an unexamined question – does drinking coffee directly triggers a migraine?

This was a rigorous prospective study of 98 adults with episodic migraine who completed electronic diaries every morning and evening for a minimum of 6 weeks. 86 participants were women and 12 were men, with mean age of 35 and the average age of onset of headaches of 16. Every day, participants reported caffeinated beverage intake, other lifestyle factors, and the timing and characteristics of each migraine headache. The researchers compared incidence of migraines on days with caffeinated beverage intake to the incidence of migraines by the same individual on days with no intake. In total, the participants reported 825 migraines during 4467 days of observation.

There was a significant association between the number of caffeinated beverages and the odds of migraine headache occurrence on that day. This association was stronger in those who normally drank 1-2 cups of coffee daily – they were more likely to get a migraine on days when they drank 3 or more cups.

Even after accounting for daily alcohol intake, stress, sleep, activity, and menstrual bleeding, 1-2 servings of caffeinated beverages were not associated with headaches on that day, but 3 or more servings were associated with higher odds of headaches, even after accounting for daily alcohol intake, stress, sleep, activity, and menstrual bleeding. The researchers also considered the possibility of reverse causation, meaning that people might have drank coffee to treat a headache, but this was also not the case.

My advice to migraine sufferers is to drink not more than 1 cup of coffee a day, and I don’t mean a Venti (24 oz) cup from Starbucks, but an 8-ounce cup of regular strength coffee. During a migraine attack having an extra cup along with your usual medication may provide additional relief.

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Keeping a diary of symptoms has long been considered a part of a successful approach to managing migraine headaches. The diary can help identify potential migraine triggers and contributing factors and a description of specific symptoms can help tailor individual therapy.

An article just published in Wired magazine Why tracking your symptoms can make you feel worse, challenges this assumption.

In my early years of practicing headache medicine (yes, “headache medicine” is a formal subspecialty of neurology) I would urge my patients to keep a diary, but they would have all kinds of excuses why they did not. I even developed a phone app, which was easy to use and was loaded with features and educational materials. Everyone always has their phone nearby, so unlike with a paper diary, they would not forget it at home or need a pen, or have it eaten by their dog. Nothing doing. Maybe, one in 10 of my patients attempted to keep a diary. Then, since I also have migraines, I tried using the app and I also failed miserably. My excuses? Forgot, too busy, I know all about my migraines, so what’s the point?

The article in Wired quotes research that suggests that keeping a diary of symptoms can make you feel worse. This seems to be true across different conditions – insomnia, back pain, and also migraine. One possible explanation is that constantly paying attention to sensations in the body we can magnify them. These sensations may send an alarm to the brain, oh-oh, a migraine is starting. This in turn leads to anxiety, activation of the fight-or-flight response and soon a real migraine begins. Actually, when a patient comes in with pages and pages of notes that describe each migraine attack with possible triggers, detailed description of each attack, medications taken and their side effects, I know that this patients will be harder to help.

In case of migraine headaches we do have a very good substitute for a daily diary. It is a Migraine Disability Assessment Scale, or MIDAS, which assesses migraine-related disability over the previous three months. This is a simple 5-question scale that was validated by comparing a daily diary with patient recollection. Surprisingly, the correlation was very strong and the scale gives reliable information. We ask patients to complete MIDAS on every visit. At a glance, it tells us how disabling the migraines are and how aggressive we need to be in starting preventive therapies, such as Botox, drugs, and the new monoclonal antibodies. This score is also helpful for patients who may not remember how disabling the headaches were before they started a particular treatment. It also shows the insurance companies how well an expensive treatment such as Botox works, so that they approve continued therapy.

As far as identifying triggers, most are obvious and patients do not need a diary to tell them that alcohol, lack of sleep, skipping meals, stress, etc. are causing their attacks. Yes, for some patients a diary can identify gluten sensitivity, menstrual cycle, or another trigger that was not obvious, so I would not discourage anyone from keeping a diary. But do it for a few months and if no useful information can be gleaned from it, stop.

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