For years researchers have tried to find ways to block various chemicals (neurotransmitters) released during a migraine attack, including serotonin, CGRP, nitric oxide, substance P, glutamate, and other. Triptans (such as IMitrex or sumatriptan), the first “designer” drugs for migraine, which were developed over 20 years ago, bind to a very specific subtype of serotonin receptor and are very effective in stopping a migraine attack.

A very promising new type of migraine medications is being developed by at least four different companies – Alder, Amgen, Eli Lily, and Teva. These drugs are monoclonal antibodies against the CGRP molecule or the CGRP receptor. CGRP (calcitonin gene-related peptide) is widely distributed in the body and is involved in regulating blood vessel opening and in the function of the nervous system. All four companies developing these drugs recently presented the results of their phase II clinical trials and the data looks very promising. The antibody tightly binds to its target (CGRP molecule or receptor) with the effect lasting a month, or in case of the Alder drug, up to 6 months. The Alder drug is given every six months intravenously, while the other three, are given every month by an injection into the muscle.

All four drugs appear to be very effective in preventing migraine attacks when compared to a placebo injection. And fortunately, at least so far, they all look very safe. However, in phase II trials only a couple of hundred patients are treated and we need to await the results of the larger and more definitive phase III trials to confirm the safety and efficacy of this new group of medications. This means that the earliest we will see these drugs approved by the FDA is in about 3 years.

It is possible that these drugs will be effective not only for the prevention of migraines, but also for stopping an acute migraine attack.

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An opening between the left and the right side of the heart, called patent foramen ovale (PFO), is found in 25% of the general population. It has been found to be more common in people who suffer from migraines. A large PFOs can cause shortness of breath, heart failure, and strokes and they are usually closed surgically. Several companies developed a device to close this opening without open heart surgery, but rather by inserting an umbrella-like device through a vein in the groin.

The manufacturers of these devices have conducted clinical trials in the hope of preventing migraines by closing the PFO. The results so far have been mixed with some studies showing improvement in migraines and some showing no benefit. A study just presented at the annual meeting of the American Headache Society by Dr. Andrew Charles of UCLA and his colleagues reported on one such trial. This study was blinded, with 107 patients having a sham procedure (the catheter was inserted into the groin vein, but the PFO was not closed) and 123 having their PFO closed. Overall, there was a significant reduction in headache days in the closure group (-3.4 days) compared with the sham group (-2.0 days), however there was no difference in the primary efficacy endpoint of the number of patients with 50% or more reduction in migraine attacks.

A subset of patients did particularly well compared to the sham group – patients who had migraine aura with the majority of their migraine attacks. A significant reduction in migraine days was present in half of patients with aura compared with a quarter in the control group. About 11% (8 out of 74 patients) of those who had migraine with aura had complete elimination of migraine attacks, while this happened to only 1.5% (1 out of 68 patients) in the sham group with auras.

This study suggests that patients who have auras with the majority of their migraine attacks and whose migraines are difficult to control should undergo an echocardiogram to test for the possible presence of a PFO. If PFO is present, it may be reasonable to consider seeing an interventional cardiologist to close the PFO. This is a relatively safe procedure if done by an experienced doctor and that is a very important if. Pick a doctor who has done a hundred or more of these procedures.

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Several presentations at the annual meeting of the American Headache Society held in Washington DC last weekend discussed the treatment of post-concussion symptoms in children (everything below also applies to adults). Among many topics, the speakers addressed the question of aerobic exercise after the concussion. Most experts agree that starting physical exercise too early can worsen the symptoms and delay recovery. At the same time, because aerobic exercise has so many benefits for the brain, it is prudent to begin aerobic exercise 2 to 4 weeks after the concussion. The child should begin exercising for short periods of time and at low intensity. Exercise should be stopped as soon as symptoms, such as headache or dizziness worsen. Brisk walking could be the first activity to be tried. The ideal duration is about 30 minutes and when this goal is achieved, the intensity of exercise can be gradually increased.

As far as the very common cognitive problems after a concussion, the experts also agreed that complete cognitive rest is not helpful. Just like with physical exercise, it is best to begin mild activities, such as reading for pleasure, and then slowly increase the load, as tolerated.

Several scientific presentations reported that the most common type of headaches that occurs after a concussion is migraine. When these post-concussion migraines last for more than 3 months and occur on more than 15 days each month, they are considered to be chronic migraines.

The treatment of post-concussion chronic migraines is the same as the treatment of chronic migraines that occur without a concussion. These treatments may include cognitive behavioral therapy, biofeedback, magnesium and other supplements (magnesium deficiency is found in up to 50% of migraine sufferers and magnesium is depleted by trauma), various preventive medications, and Botox injections.

Although the FDA has not yet approved Botox injections for the treatment of chronic migraines in children, Botox is safer than most drugs. We know about the safety of Botox in children because it has been widely used even in very young children who suffer from cerebral palsy and are unable to walk unless their stiff leg muscles are relaxed by Botox. Botox was approved by the FDA 26 years ago and some kids have been getting injections for over 20 years and so far there have been no long-term side effects observed.

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Zolmitriptan is one of seven triptans available in the US and it comes in tablets (Zomig), orally disintegrating tablets, that is tablets that melt in your mouth (Zomig ZMT), and nasal spray (Zomig NS). The nasal spray was just approved for children 12 and older. It is available in 2.5 mg and 5 mg strength and the 2.5 mg is the starting dose, but kids are allowed to take 5 mg dose up to twice a day.

My previous post mentioned the approval of Treximet, a combination of sumatriptan (Imitrex) and naproxen (Aleve) in adolescents. However, Zomig is the only triptan in a nasal spray form (the second triptan available in a nasal spray is sumatriptan or Imitrex) approved in the US for children. The advantages of this form of drug delivery is that it tends to have faster onset of action and it can be taken when severe nausea or vomiting precludes the use of oral medications. Sumatriptan nasal spray is approved in kids in Europe, so there is no reason not to use it as well, however Zomig spray seems to be better than Imitrex spray. The amount of fluid in a single dose of Zomig is less than that in Imitrex and the spray droplets are of smaller size, leading to better retention of fluid in nasal passages and better absorption. Also, many patients complain of a very unpleasant taste with Imitrex spray, although this can be avoided by sucking on a hard candy while spraying. This will carry the saliva out of the mouth down the throat and the drug will not reach the mouth. When using nasal sprays it is important not to sniff them up your nose because this will carry the medicine into the throat rather than having it stay in the nose where it gets absorbed faster.

Since we are on the topic of nasal sprays, I should mention three other nasal sprays that can be used to treat headaches. Migranal nasal spray contains dihydroergotamine, which is one of the strongest injectable migraine medications. However it is a lot less effective in a nasal spray form. Sprix is a nasal spray of ketorolac (Toradol), a nonsteroidal anti-inflammatory drug, which is also much stronger when injected. It is also available in a tablet, but the tablet is not any stronger than aspirin or ibuprofen. The third nasal spray is Stadol NS and it contains butorphanol, a strong narcotic pain killer. It should be avoided because it is very addictive.

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A combination pill containing 10 mg of sumatriptan with 60 mg of naproxen sodium was just approved by the FDA for children aged 12 to 17. This combination in a higher dose (85 mg of sumatriptan and 500 mg of naproxen) has been available for adults for the past 7 years. This recent FDA approval allows children to take up to one adult strength tablet a day. It is good to have a smaller size tablet for kids. However, there is a big issue of cost. We don’t yet know what the pediatric strength tablet will cost, but a single tablet of the adult strength Treximet is $75. Yes, $75 for one tablet, even with a coupon you can get at GoodRx.com and $80 or more without a coupon. Very few insurance companies will pay for Treximet because you can get a generic tablet of sumatriptan (Imitrex), 100 mg for $1.50 and a tablet of naproxen, 500 mg for 7 cents. So, make-your-own Treximet will cost you $1.57. A very rare patient will tell me that they get better relief from the branded pill, which is possible because of the inactive ingredients, speed of onset and occasionally poor quality generics (I wrote about this problem in a previous post). However, such patients are very few.

Besides Treximet, we have two other triptans approved for migraines in children. Rizatriptan (Maxalt, Maxalt MLT) is approved by the FDA for children and adolescents 6 to 17 years of age and it is available in a generic form. Almotriptan (Axert) is approved in adolescents, 12 – 17 years of age, but it is available only as a branded drug ($40 a pill). In the UK, 10 mg sumatriptan nasal spray (Imitrex in the US, Imigran in the UK) was approved for adolescents, ages 12-17, who suffer from migraine and cluster headaches. In the US, we have only 5 and 20 mg nasal sprays of sumatriptan, and both are available in a generic form. Sumatriptan and zolmitriptan (Zomig, Zomig ZMT – orally disintegrating tablet, Zomig NS – nasal spray) were also tested in kids. The reason these two drugs were not approved is because the placebo response in kids tends to be very high and the active treatment was not distinguishable from placebo. This is mostly because headaches in children tend to be shorter in duration and the headache goes away on their own in a couple of hours, making it difficult to separate the active drug from placebo. However, they are probably as effective and as safe as the triptans approved in pediatric patients.

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Transcranial magnetic stimulation (TMS) was approved by the FDA at the end of 2013 (see my earlier post) but it has not yet become available. This approval was for the treatment of acute migraine.

A new study just presented at the International Headache Congress suggests that TMS could be effective for the preventive treatment of migraines with medication overuse headache.

The study included only 28 patients and it was not a blinded study. However, these patients were severely affected and failed several other treatments. They were instructed to use the TMS device twice a day every day with an additional treatment at the time of a headache. Treatment lasted for at least 3 months, with an option to continue for another 3 months.

Of the 28 patients, 24 (86%) reported a reduction in their days of acute medication use per month, while 2 patients reported an increase in acute medication use. Nineteen patients (68%) experienced fewer migraine days per month, and 7 of the 19 had a 50% or greater reduction in migraine days. The number of patients with pain severity rated as excruciating or severe dropped from 19 at baseline to 3 at 3 months (84% reduction). Headache attack duration decreased in 15 patients, remained unchanged in 9, and increased in 4. The disability score (HIT-6) was severe at the beginning of the study in 26 of 28 participants. After 3 months, only 18 had severe disability.

The benefit was seen in patients who had migraines with and without aura.

After 3 months, five patients stopped using TMS because it was ineffective or inconvenient. Four were lost to follow-up. Of the remaining 19, 16 reported reduced days of acute medication use at 6 months, compared with baseline. Disability scores in the 19 patients who used TMS for 6 months were comparable to their scores at 3 months, suggesting that there was no additional benefit from longer-term use, but the benefit was maintained.

No side effects were reported, confirming the safety of TMS. Now we just have to wait for the company (eNeura) to release this product on the market.

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We are again in a cluster season. We do not see any cluster headache patients for months and then dozens come in within weeks. It is not allergies, barometric pressure or any other earth phenomena that trigger cluster headaches in so many people at once. It has been speculated that solar activity may be the trigger and I just checked the NASAs Solar Dynamics Observatory website and found that the sun has “active regions galore”. I wrote about solar activity as a possible culprit last October when we had another wave of cluster patients. Unfortunately, there is not much we can do about the sun, but we do have many effective treatments for cluster headaches, including intravenous magnesium, occipital nerve blocks, oxygen, injectable sumatriptan, verapamil, and for chronic cluster headaches, Botox injection.

A recent study by British neurologists in the journal Headache described the severe impact of cluster headaches on quality of life and neuro-psychological symptoms. The researchers found that cluster headache patients had normal intelligence and executive functions, but had worse working memory, disturbance of mood, and poorer quality of life compared with healthy controls. Similar findings have been found in patients with other chronic pain conditions as well. It is most likely that cognitive impairment and mood changes can be reversed with effective treatment of pain.

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Another supplement to consider for the preventive treatment of migraine headaches is diamine oxidase (DAO). It is an enzyme that breaks down histamine.

Histamine is released during an allergic reaction and is present in many foods. It is one of the neurotransmitters that is involved in the process of migraine. A quarter of the population has insufficient amounts of DAO, which leads to inefficient metabolism of histamine. The largest amounts of DAO in the body are found in the intestines and the kidneys.

A group of Spanish neurologists published a study that showed that of 137 patients with migraines, 119 (87%) showed impaired activity of the enzyme.

The normal enzyme activity is a score of at least 80 histamine-degrading units [HDU]/mL. In a survey which was conducted in 2006 and again in 2012, migraine symptom scores correlated with enzyme activity. Symptom scores rose progressively as enzyme activity dropped below 80 HDU/mL, with scores almost twice as high in the 30-40 HDU/mL range compared with enzyme activity >80 HDU/mL.

Dr. Izquierdo and his colleagues in Barcelona conducted a double-blind, placebo-controlled trial of DAO oral supplementation, for the prevention of migraines in patients with DAO activity less than 80 HDU/mL.

Participants were men or women age 18 to 60 years old with an attack within the previous 6 months. Most of the patients were women, with only 8 men in each group.

The supplement contained 4.2 mg of DAO which participants took with a glass of water before breakfast, lunch, and dinner. The supplement was associated with a similar reduction in the mean number of attacks per month in the placebo and DAO groups, but the group that took DAO used significantly fewer triptan drugs (such as sumatriptan, Imitrex). These results are not overwhelming, but they possibly hide the fact that some of these patients had a very good response while others had none, which averaged out to a modest benefit. Considering that this a very benign supplement with no potential for serious side effects (unlike prescription drugs), it may be worth trying.

Histamine intolerance is defined by an imbalance of histamine and the histamine degrading enzyme diamine oxidase (DAO), which is mainly produced in the small intestine. Excessive amounts of histamine in the body can cause not only migraine and other types of headaches, but also diarrhea, nasal congestion, asthma, rashes, and other symptoms. People who are prone to severe allergic reactions with anaphylactic shock often have lower DAO activity. Diamine oxidase activity can be measured in blood, but the test is expensive and not very reliable. Instead of doing this test, try a low histamine diet or taking a DAO supplement. This is particularly worthwhile for people who in addition to migraines suffer from colitis (such as Crohn’s), allergic conditions, asthma, and celiac disease.

Here is an informative post on this topic on The Daily Headache blog.

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Tension headaches can be prevented, or at least made milder by strength training, according to a new Danish study just published in the journal of the International Headache Society, Cephalalgia.

Tension-type headache is the most common type of headaches and it is usually accompanied by increased muscle tenderness.

The researchers compared muscle strength in neck and shoulder muscles in 60 patients with tension-type headaches and 30 healthy controls, using rigorous strength measurement techniques. Patients were included if they had tension-type headaches on more than 8 days per month and had no more than 3 migraines a month. Compared to controls headache patients had significantly weaker muscle strength in neck extension, which helps keep the head straight. Headache patients also showed a tendency toward significantly lower muscle strength in shoulder muscles. Among the 60 headache patients, 25 had frequent headaches and 35 had chronic tension-type headaches (defined as occurring on 15 or more days each month).

The use of computers, laptops, tablets, and smart phones has increased in recent years and this may increase the time people are sitting with a forward leaning head posture, which contributes to neck muscle weakness.

Neck pain and tenderness is a common symptom in both tension-type and migraine headache sufferers.

This is not the first study to show that muscle strength and weakness were associated with tension-type headaches, but it is still not clear whether the muscle weakness is the cause or the effect of headaches. Neck and shoulder strengthening exercises have been shown to reduce neck pain in previous studies and in my experience strengthening neck muscles will often relieve not only tension-type headaches, but also migraines. So it is most likely that there is not a clear cause-and-effect relationship, but a vicious cycle of neck pain causing headaches and headaches causing worsening of neck pain and neck muscle weakness.

Physical therapy can help, but the mainstay of treatment is strengthening neck exercises. Here is a YouTube video showing how to do them. The exercise takes less than a minute, but needs to be repeated many times throughout the day (10 or more). Many people have difficulty remembering to do them, so using your cell phone alarm can help. Other treatment measures include being aware of your posture when sitting in front of a computer or when using your smart phone, wearing a head set if you spend long periods of time on the phone, doing yoga or other upper body exercises, in addition to the isometrics.

Sometimes pain medications or muscle relaxants are necessary, while for very severe pain, nerve blocks and trigger point injections can help. Persistent neck pain can respond to Botox injections. When treating chronic migraines with Botox, the standard protocol includes injections of neck and shoulder/upper back muscles. Here is a video of a typical Botox treatment procedure for chronic migraines.

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While Botox (OnabotulinumtoxinA) has been shown to be effective in treating chronic migraines, its exact mechanism of action is not clear. Initially, we thought that it works by relaxing muscles in the forehead, temples and the back of the head and neck. However, this is not likely for several reasons. One reason is that some people have pain at the top of their heads, where there are no muscle, and injecting those areas leads relief of pain. Another reason is that Botox seems to be effective in relieving different nerve pains, such as that of shingles (post-herpetic neuralgia), trigeminal neuralgia, and other.

Botox blocks the release of acetylcholine, a neurotrasmitter that is normally released into the space between the nerve ending and the muscle (synapse), making the muscle contract. We also know that Botox blocks the release of other neurotransmitters, which may be responsible for its pain-relieving properties. One of these chemical messengers is CGRP (calcitonin gene-related peptide).

A study just published in the journal Pain by Spanish researchers showed that CGRP level is increased in blood of patients with chronic migraine even when they are not having a migraine attack. CGRP levels were determined in 83 patients with chronic migraines (average age 44 years; 94% females) before and 1 month after treatment with 155 to 195 units of Botox. CGRP levels after Botox treatment were significantly lower as compared with CGRP levels obtained before Botox treatment. Pretreatment CGRP levels in responders were significantly higher than those seen in nonresponders. One month after treatment, the CGRP levels did not change in nonresponders, but significantly decreased in responders. Demographic factors, clinical features, and comorbidities (co-existing medical conditions) were not different in responders as compared with those of nonresponders. The authors concluded that “These results confirmed that CGRP levels can be of help in predicting the response to Botox and suggest that the mechanism of action of Botox in chronic migraine is the reversal of sensitization as a result of the inhibition of CGRP release.”

Unfortunately, the test to measure CGRP levels is not yet available outside research laboratories and because this was a small study we do not know how accurate this test will be. It has to tells us with greater than 90% which migraine sufferer will respond. If it is less than 90% accurate, we’d be denying over 10% of patients a very effective and often life-altering treatment. Some studies also suggested that we can predict who will respond and who will not by the description of pain. That is, if the pain is squeezing, crushing from outside in, or involves the eye, then the chances of response are better than if the pain is exploding, or from inside out. The accuracy of this predictor is less than 70%, so it should not be used to screen for potential non-responders.

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