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Migraine

The role of vitamin B12 is underappreciated by many doctors. This week, The Wall Street Journal published a full-page article on vitamin B12 deficiency, which can be of great help to many of the two million readers of this newspaper. The survey quoted in the article shows that only one third of patients with this deficiency are diagnosed within a year, 22% within 1-2 years, 20% within 2-5 years 10% within 5-10 years and 14% after more than 10 years. It took several years for the author of the WSJ article to be diagnosed.

A confounding problem is that even if the doctor orders a vitamin B12 level, the widely used blood test is inaccurate. While the normal range is from 200 to 1,200 (depending on the laboratory), cases of severe deficiency have been described with levels of up to 700. You may have a good amount of vitamin B12 circulating in the blood, but it may not be getting into the cells where it is needed for the normal functioning of the nervous system, blood formation, and other functions. Many patients with a level above 200 are told by their doctors that their level is normal, but it should be at least over 400 and even better if it is above 500. We do have two additional blood tests that can confirm if the body needs additional vitamin B12 – homocysteine and methylmalonic acid levels but they are rarely utilized.

It is well worth your time to read the entire WSJ article.

I’ve written several times about the dangers of long-term treatment with PPIs, acid reducing drugs, such as Prilosec and Nexium. Among other side effects, they interfere with the absorption of vitamin B12 and other vitamins and minerals.

As far as headaches, vitamin B12 deficiency can be a contributing factor and taking vitamin B12 along with other B vitamins can relieve migraines.

Pain of facial neuralgia was found to be due to vitamin B12 deficiency in case studies of 17 patients and their pain resolved with vitamin B12 injections.

As the WSJ article suggests, many patients with neurological symptoms require regular injections rather than taking vitamin B12 pills. A couple of hundred of our patients come for monthly vitamin B12 injections, often along with an infusion of magnesium – another very common and highly underdiagnosed deficiency. It is not only migraines and other headaches that improve, but also fatigue, dizziness, and other symptoms.

Here is an old article from the Educational Materials section of our website.

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Migraine is rightfully considered a women’s health issue since of the more than 39 million Americans with migraines, 28 million are women. But 11 million is still a lot of men. Unfortunately, men do not seek help as often as women do and we see this in our office and in clinical trials of new drugs for migraines, where the ratio is closer to 1 to 10.

Today’s Wall Street Journal has an article, Why Men Won’t Go to the Doctor, and How to Change That, which addresses some of the reasons.

The article notes that men are notoriously bad patients. In our office, it is usually a mother, a wife, or a girlfriend who brings the man to the office. Men consider complaining of a headache or any other symptom a sign of weakness. They just grin and bear until they are totally incapacitated. This is probably one of the reasons why women live longer.

Fortunately, migraines are not life-threatening but they can certainly ruin relationships, affect job performance, cause depression and other problems. Men are often reluctant to share their feelings and see a therapist and have higher suicide rates than women.

Men tend to be not very compliant with treatment and are more likely to come in for Botox injections every 3 months rather than take a pill every day. In this case they are acting rationally since any oral medication has more potential side effects than Botox. Regular exercise, which is at the top of my list of preventive therapies, also tends to appeal to men, but my second recommendation, meditation much less so.

Men are more receptive to the idea of taking a shot for their problem and here they are also correct – taking an injection of sumatriptan (Imitrex) stops an attack of migraine within 10-20 minutes, while a pill of sumatriptan can take up to two hours and may not work as well.

The new class of CGRP monoclonal antibodies (Aimovig, Ajovy, Emgality) also obviates the need for taking a pill every day – they are injected once a month (Ajovy can be injected every three months) to prevent migraines.

The bottom line – if you know a man who admits to having headaches, chances are they are suffering more than they let on. Tell them to see a headache specialist.

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Haloperidol (Haldol) is a psychiatric drug prescribed  for the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, nausea and vomiting, delirium, agitation, and acute psychosis.

A cases series published in The Journal of Emergency Medicine in 1995 described six patients who presented with a severe migraine to an emergency room in Toronto and were given haloperidol intravenously. Within an hour all six were either pain-free or significantly improved and none returned to the emergency room within 48 hours.

A double blind placebo controlled study published by Finnish researchers in the journal Headache in 2006 examined the efficacy of 5 mg of haloperidol given intravenously in the treatment of severe migraines. Forty patients were enrolled in the study and 80% (16 patients out of 20) of those who received haloperidol had significant pain relief, compared with 15% (3 patients) in the placebo group. Because the majority of patients had taken regular NSAIDs analgesics and triptans without response, the authors concluded that haloperidol appears to be effective in treatment resistant migraine attacks. However, almost all patients who receive haloperidol complained of side effects, mostly sedation and unpleasant restlessness (akathisia). The side effects were mild to moderate in severity and reversible. The restlessness can be relieved by diphenhydramine (Benadryl).

Haloperidol is one of the neuroleptic drugs, a category that includes droperidol and phenothiazine drugs such as chlorpromazine mentioned in an earlier post. All these drugs have the potential to cause serious and in rare cases permanent neurological side effect of involuntary movements. This is why they are mostly used when other acute migraine therapies have failed. The neurological side effects are more common with continued daily use of haloperidol and other neuroleptics in psychiatric disorders.

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Granisetron (Kytril, Sancuso) is one of the anti-nausea medications in the family of setrons. Ondansetron (Zofran) and palonosetron (Aloxi) are the other two drugs in this family available in the US. These drugs are approved for the prevention and treatment of chemotherapy-induced and post-surgical nausea and vomiting, but are also used to treat nausea of migraine attacks.

Granisetron was found to relieve nausea as well as pain in one anecdotal observation of 7 patients and two controlled trials.

The first study was conducted in Canada and it involved 28 patients who presented to the emergency department with an acute migraine. This was a randomized, double-blind, placebo-controlled study of intravenous granisetron (40 micrograms/kg or 80 micrograms/kg). Significant improvement in headache pain was observed in the 80-micrograms/kg group. Except for more nausea at 30 min in the placebo group, no significant differences were noted between treatments. The authors concluded that “granisetron may be effective for acute migraine headache; however, further studies with increased patient numbers are required.”

The second Iranian study was also conducted in an emergency room and included 148 patients. The doctors compared intravenous granisetron, 2 mg with intravenous metoclopramide, 10 mg. They found that the drugs were equally effective in the treatment of nausea, but granisetron was somewhat better at relieving pain.

The general consensus is that setrons are not very effective for the treatment of migraine pain, while metoclopramide (Reglan) and phenothiazine drugs, such as prochlorperazine (Compazine), promethazine (Phenergan) and chlorpromazine (Thorazine) relieve both nausea and pain. However, setrons have the advantage of not having the potential to cause serious neurological side effects. These include severe restlessness and involuntary movements (tardive dyskinesia), which in rare cases can become permanent.

We do treat patients with an acute migraine in the office and after an infusion of magnesium usually start with ondansetron and a pain medicine such as ketorolac (Toradol), but in some people, metoclopramide is consistently more effective. If metoclopramide causes restlessness, intravenous diphenhydramine (Benadryl) almost always stops it.

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by Molly Rubin, a video journalist at Quartz. Quartz is a digital news site founded by the Atlantic. This is a very well done video news piece on migraines.

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Patients suffering from migraine with aura (MA) are at a higher risk of strokes. It is not clear what leads to this problem. Elevated homocysteine level increases the risk of strokes and heart attacks and patients with MA are more likely to have this abnormality. Another possible explanation is reported in a recent study mentioned on this blog in December, This study convincingly argues that the risk of stroke is increased because of the higher incidence of a certain type of cardiac arrhythmia, atrial fibrillation in patients with MA.

Researchers at the University of South Carolina recently discovered that the risk of strokes is higher only in migraine sufferers who started having migraines after the age of 50.

The findings were a part of the Atherosclerosis Risk in Communities (ARIC) study. Among 11,592 black and white participants, 447 had MA and 1,128 MO. The risk of stroke in those whose MA began after the age of 50 was double that of those with no headaches. MA that started before 50 was not associated with stroke. MO was not associated with increased stroke regardless of the age of onset. The absolute risk for stroke in migraine with aura is 8% and migraine without aura is 4%.

To reduce the risk of strokes (whether you have migraine with aura or not) you need to keep your cholesterol under control, not smoke, exercise regularly, maintain good blood pressure and weight.

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Galcanezumab (Emgality) was the third drug in the family of CGRP monoclonal antibodies (mAbs) to become approved by the FDA for the prevention of migraines. It is more similar to fremanezumab (Ajovy) in its mechanism of action than to erenumab (Aimovig). Erenumab is an antibody that blocks the CGRP receptor, while galcanezumab and fremanezumab are antibodies that block the CGRP molecule. This may explain the fact that some patients who do not respond to one of these drugs may respond to another. Actually, even patients who do not respond or respond only partially to fremanezumab may respond to galcanezumab and the other way around. This should not be surprising since many drugs with the same mechanism of action may have different efficacy and side effects in different patients. In migraine treatment this applies to triptans, such as sumatriptan (Imitrex), rizatriptan (Maxalt), eletriptan (Relpax), and other, as well as beta blockers, such as propranolol (Inderal), atenolol (Tenormin), nebivolol (Bystolic).

Just like the other two CGRP mAbs, galcanezumab is injected monthly (although fremanezumab can be also given at a triple dose every three months). The initial dose is 240 mg, or two auto-injector pens, followed by a monthly dose of 120 mg. The main side effects are similar to the other two drugs, namely injection site reactions such as swelling, redness, and an allergic rash. Erenumab can be constipating, while the other two drugs are much less so.

The cost of all 3 drugs is the same – between $550 and $600 per monthly injection, but most insurers will pay for them if certain conditions are met. The main condition is that the patient first try and fail two oral preventive medications such as beta blockers listed above, an antidepressant such as amitriptyline (Elavil), nortriptyline (Pamelor), or duloxetine (Cymbalta), or an epilepsy drug such as topiramate (Topamax) or divalproex sodium (Depakote).

Another, more recent requirement from many insurers, is that the patient not be receiving Botox. This prohibition is very upsetting because it is not based on any science and because many patients find that together these treatments (Botox and a CGRP mAb) provide almost complete relief of their migraine attacks. Both Botox and CGRP mAbs can be life-changing on their own with dramatic relief in about 20% of patients, while another 50% of patients obtain only partial relief. This is a very rational combination because these treatments work in a totally different way and both are extremely safe with no drug interactions. The insurers justify their refusal by the fact that there are no published studies showing the safety of this combination, which is ludicrous. Some insurers, such as Cigna, go a step further in their obnoxiousness – even if a patient gets free mAb from the manufacturer or pays out of pocket, they refuse to pay for Botox. How do they know if the patient is getting a mAb? – to get prior approval for Botox we have to submit our medical notes.

All three manufacturers of mAbs, Amgen, Teva, and Eli Lilly provide up to one year of free medicine if your commercial insurance refuses to pay for it. Check each manufacturer’s website – Aimovig.com, Ajovy.com, and Emgality.com. Allergan, Botox manufacturer offers up to $700 off each quarterly treatment, so if you are paying out-of-pocket or have a high copay or deductible, check BotoxSavingsProgram.com 

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Yet another study shows that low vitamin D level predisposes to neurological problems. A report just published in a leading neurology journal, Neurology by British and American researchers shows that low levels of vitamin D are associated with a higher risk of delirium in hospitalized patients.

This study looked at 313,121 participants, 544 of whom were hospitalized with delirium. The researchers proved that there is genetic evidence supporting connection between vitamin D levels and delirium. They called for trials of correction of low vitamin D levels for the prevention of delirium.

It is a strange call to action because we already know from other large studies that vitamin D deficiency predisposes to several neurological problems. These include not only migraines, but also multiple sclerosis, stroke, and other major diseases  Why not just make sure that nobody has a deficiency? Well, one reason is that insurance companies do not want to pay for the test because we do not have proof that correcting this deficiency will prevent these neurological problems. As we know, correlation does not mean causation. However, conducting large scale studies is very expensive and it takes many years to obtain the results. And why was a normal range for vitamin D was established if not to make sure that people are not deficient.

As I mentioned in my last post on vitamin D in 2015 everyone should have their vitamin D level checked and if you are deficient, get your level up to the middle of normal range. The normal range is 30 to 100, so below 40 is definitely not optimal.

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Ginger is not only a popular spice, but a truly remarkable medicinal plant. Ginger’s proven anti-inflammatory properties may be responsible for its beneficial effects in migraine patients. Ginger may be effective for the treatment of seasickness, morning sickness of pregnancy and I recommend it for nausea of migraine as well.

A study published in the journal of the International Headache Society, Cephalalgia examined the effect of ginger, when added to an intravenous pain medication.

This was a double-blind placebo-controlled randomized clinical trial performed in the emergency room of a general hospital in Brazil. Adults who suffered from migraines with or without aura one to six times per month were included. Half of the sixty participants were given 400 mg of ginger extract (5% active ingredient) or placebo, in addition to an intravenous drug (100 mg of ketoprofen, a drug not available in the US in an injection, but it is similar to ketorolac, or Toradol) to treat an attack of migraine. Pain severity, functional status, migraine symptoms and treatment satisfaction were recorded.

Patients treated with ginger showed significantly better pain relief after 1, 1.5 and 2 hours. Ginger also significantly improved functional status and overall satisfaction.

Another double-blind study involving 100 patients compared the efficacy of ginger with sumatriptan in the treatment of an acute migraine attack. Patient satisfaction and their willingness to continue treatment was also evaluated after 1 month following intervention. Two hours after using either drug, mean headaches severity decreased significantly. Efficacy of ginger powder and sumatriptan was similar. Adverse effects of ginger powder were less than sumatriptan. Patient satisfaction was similar in two groups.

Considering that ginger has anti-inflammatory properties, it is possible taking it daily may also prevent migraines, although no preventive trials have been conducted to date.

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Gabapentin (Neurontin) is a drug that was originally developed for the treatment of epilepsy but now it is used for a wide variety of conditions except for epilepsy. It is just not strong enough to control epileptic seizures. Gabapentin can be effective for various pain syndromes, including the treatment of sciatic pain and it has an official FDA approval for the treatment of a very painful condition, postherpetic neuralgia, or shingles pain.

Several positive studies of gabapentin have been also reported for the treatment of episodic as well as chronic migraines. However, a review of all rigorous clinical trials of gabapentin for the treatment of migraine found no evidence that it really works. The authors of the review concluded that, “Since adverse events were common among the gabapentin-treated patients, it is advocated that gabapentin should not be used in routine clinical practice”. The adverse events were mostly dizziness and somnolence.

My personal experience also suggests that gabapentin is not highly effective and I do not use it “in routine clinical practice”. However, because gabapentin is proven to relieve other painful conditions and because it has a relatively benign side effect profile, I do use it in some patients with migraine, especially those with associated neck pain. It can also help patients with insomnia, although this indication is also not proven in large trials.

Gabapentin is used in doses of up to 3,600 mg a day and higher, although there have been reports of gabapentin abuse and dependence at doses above 3,000 mg a day. We usually start with 300 mg a day and slowly escalate the dose as needed and as tolerated to about 1,800 mg a day. Some patients report good relief of insomnia with 300 mg taken at night. Transition to menopause can be accompanied by temporary worsening of migriane headaches and gabapentin can also help menopausal hot flashes (and sleep) at a dose of 900 mg a day.

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To be eligible for this study you have to live in NYC or its suburbs and cannot be currently receiving Botox or a CGRP monoclonal antibody, such as Aimovig, Ajovy or Emgality.

PARTICIPATE IN MIGRAINE RESEARCH
A RANDOMIZED SHAM-CONTROLLED STUDY OF HOME-DELIVERED NON-INVASIVE NEUROSTIMULATION FOR MIGRAINE

• If you have frequent headaches (on 4 days or more/month) you may be eligible to enroll in a study of non-invasive neurostimulation aiming to reduce migraines.
• Neurostimulation provides stimulation of the nerves in the human body. Frequently used neurostimulation methods are for example, acupressure, acupuncture or TENS.
• This study uses a new neurostimulation method, tDCS. tDCS is a battery-powered device that delivers stimulation via two sponge pockets placed to a simple headband. Study participants will be assigned either to a group receiving active tDCS or to a control group receiving placebo tDCS.

If you are interested in more information about the study, please call the study personnel at 212-794-3550 or 212-440-1954 or email DrMauskop@nyheadache.com

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Cefaly is a transcutaneous electrical nerve stimulation (TENS) device designed to treat migraine headaches by stimulating supraorbital nerves. The device was cleared by the FDA in 2014 for both acute and preventive treatment of migraine headaches. The preventive indication was based on a double-blind trial involving only 67 patients, while the use of Cefaly for acute migraines was based only on an open-label trial. A study recently published in Cephalalgia examined the efficacy of this device for acute treatment of migraines in a double-blind trial of 106 patients.

The trial confirmed that Cefaly is indeed effective for abortive therapy of migraine attacks. For prevention, it is recommended to use the device for 20 minutes every day, while to treat an acute attack the device should be used for an hour. The primary outcome measure was the mean change in pain intensity at 1 hour compared to baseline. This primary outcome measure was significantly more reduced in the stimulation group compared to the sham group: 60% versus 30% reduction. No serious adverse events were reported and five minor adverse events occurred in the stimulation group. I’ve had one or two patients report that the device actually triggered a migraine, but this can also happen with any oral migraine drug.

The main reason I offer Cefaly before any other device (eNeura TMS or gammaCore) is that it is the most affordable. The price has gone up since it’s introduction and ranges from $350 to $500, however the manufacturer offers a 60-day return policy. This is long enough to see if it is effective. Cefaly is sold only with a doctor’s prescription, which is uploaded to the Cefaly website (Cefaly.us for US patients and Cefaly.com for the rest of the world).

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