Many migraine sufferers suffer from nausea and vomiting and cannot swallow pills or even if they can swallow them, it takes too long for them to work. Injections is one way to overcome this problem, but nasal spray is a much more pleasant alternative. There are several migraine medications available in a nasal spray form, including Zomig (zolmitriptan), Imitrex (sumatriptan), Migranal (dihydroergotamine), Sprix (ketorolac), and Stadol (butorphanol). Unfortunately, they don’t always work or work inconsistently. Having nasal congestion due to allergies, a cold, or migraine itself often makes these medicines ineffective. Stadol is a narcotic, which can be addictive, while Imitrex and Migranal require delivery into the nose a large volume of fluid, which tends to leak out or gets swallowed, thus reducing their efficacy.

Seattle-based Impel Neuropharma has been working for five years to show it can quickly deliver drugs through the nose, directly to the brain, rather than what happens with the currently available sprays – absorption into the blood stream first and then carried to the brain. Impel, a University of Washington spinoff, recently presented a study of seven patients who used the company’s nose-to-brain drug delivery device, which was able to propel a test protein deep into the upper nasal passages and to the brain stem at an “order of magnitude” greater concentration than a conventional nasal spray. Researchers saw it get delivered to the destination within 10 to 20 minutes. Most nasal sprays don’t propel drugs anywhere close to the upper nasal passages, which is the only place in the body where nerve cells (neurons) are possibly accessible to the outside environment. This device delivers a pressurized, rotational flow of aerosol to reach those neurons.

The company stated that a nose-to-brain delivery device could, in theory, get an effective pain reliever to work more quickly for patients in need of something fast, and do it safely by minimizing the amount that gets absorbed into the bloodstream. It also could be convenient for patients, especially when compared with injectable treatment options.

Art credit: JulieMauskop.com

Botox appears to be effective for the treatment of chronic post-traumatic headaches in service Members with a history of mild traumatic brain injury according to a recent report by Dr. Juanita Yerry and her colleagues at Ft. Bragg, NC. The researchers assessed the safety of onabotulinum toxin type A (Botox) in the preventive care of post traumatic headache. Headache is a common complication of mild traumatic brain injury in active duty service members. Migraine and chronic migraine type are the most common headache types. The approved use of Botox in chronic migraine made the doctors think that Botox might be safe and possibly effective in post-traumatic headaches with features of chronic migraines. They examined records of all patients treated with Botox for post-traumatic headache in the Concussion Care Clinic at Womack Army Medical Center, Ft. Bragg, NC between 2008 and 2012. They recorded patient demographics, prior history of headache, injury type, current headache type, time from injury to first injection, treatment techniques, number of treatments/treatment interval, side effects, reasons for discontinuation and Patient Global Evaluation of Change (PGEC). Out of 67 patients (66 male) who were treated 10% had prior history of headaches. Most common injuries were blast (46.3%), parachute jumps (14.9%) and motor vehicle accidents (11.9%). About 56% reported more than one headache type. Headache types included: chronic migraine (22.4%), episodic migraine (7.5%), chronic tension type (7.5%), hemicrania continua (7.5%), nummular (1.5%); mixed tension/chronic migraine (41.8%), and tension/migraine (7.5%). A very large percentage (75%) had a continuous headache. Reasons for discontinuing Botox treatment included ineffectiveness (44.8%), side effects (2.9%), or reinjury (1.5%). They were not able to follow-up with 22% patients of whom 73.3% reported being “much better”. Overall, 60% were better or much better, 4.5% were worse or much worse, and 33% reported no change. The researchers concluded that Botox appears to be safe and well tolerated in active duty service members treated for post-traumatic headaches.

Art credit: JulieMauskop.com

A new treatment for pseudotumour cerebri was reported by a team of interventional neuroradiologists and neurosurgeons. Pseudotumour cerebri is a rare condition, which manifests itself by increased pressure in the head, leading to severe headaches, vision impairment and even complete loss of vision and brain damage. It affects more women than men and usually occurs without an obvious trigger, although pregnancy, obesity, and certain medications increase the risk of developing this condition. The diagnosis is made by performing a spinal tap (lumbar puncture) and measuring cerebrospinal fluid pressure. Typical MRI scan findings (narrowing of the ventricles – cerebrospinal fluid filled spaces in the brain) and finding of swollen optic nerves (papilledema)on eye exam confirm this diagnosis.

The new treatment is based on the theory that narrowing of a vein located at the back of the brain is the underlying cause, although this theory remains controversial. Narrowing of this vein is thought to reduce drainage of the cerebrospinal fluid from inside the brain, leading to build up of this fluid and increased pressure inside the skull. The usual treatments for pseudotumor include weight loss, medications that reduce pressure, such as acetazolamide (Diamox), and the surgical placement of a shunt to continuously drain spinal fluid from the brain, thus reducing the pressure.

The study, published in the online edition of the Journal of Neuro-Ophthalmology, shows that lowering pressure inside the vein alleviates the condition and improves vision. The doctors at Johns Hopkins used an advanced ultrasound scanner to thread an expandable metal stent through a vein in the groin, all the way to the transverse sinus, one of the main veins inside the skull draining fluid from the brain.

The study involved only 12 patients, but all of them had immediate relief of their headaches and 10 had lasting improvement. The researchers admitted that the efficacy of this treatment needs to be confirmed in a larger group of patients.

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Approval of the inhaled dihydroergotamine or DHE to be sold under the name of Levadex has been delayed again by the FDA. We expected approval last year because the FDA did consider the product to be safe and effective, but they were not happy with the manufacturing process. The application for approval was resubmitted and we all expected the product to become available in the middle of this year, but apparently the FDA still has the some concerns about the manufacturing. If all goes well Levadex may come to the market at the end of 2013. In the past few months the small company that developed Levadex, MAP Pharmacueticals sold itself to the maker of Botox, Allergan. Allergan hopes to find synergy between Botox, which is approved for the prevention of chronic migraines and Levadex, which is indicated for the treatment of an acute migraine attack. It will be much more efficient for Allergan’s sales force to sell two complementary drugs to neurologists rather than just one. Both are excellent drugs with high efficacy (70% for Botox and 60% – 70% for Levadex), excellent safety for Botox and relatively good safety for Levadex (comparable to triptans, such as Imitrex).

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Melatonin does seem to help prevent migraine headaches according to a new study by Brazilian researchers just presented at the annual scientific meeting of the American Academy of Neurology. In my previous post over two years ago I wrote about a negative study that showed no benefit from 2 mg of extended release melatonin given to 46 migraine sufferers. This new study was also blinded and it compared 3 mg of immediate release melatonin with placebo and with 25 mg of amitriptyline, which is one of the oldest preventive drugs for migraines.
This was a larger study – it involved 196 patients who suffered from 2-8 attacks of migraine with or without aura each month. The number of headache days dropped by 2.7 days in the melatonin group, 2.18 for amitriptyline, and 1.18 for placebo. Melatonin significantly reduced headache frequency compared to placebo, but not to amitriptyline. Not surprisingly, melatonin was better tolerated then amitriptyline. Considering its safety and very low cost, it is worth considering a trial of 3 mg of melatonin for the prevention of migraine headaches. Some studies have suggested that taking a much smaller dose of 0.3 mg (300 mcg) of melatonin may be more effective for insomnia than taking a much larger dose. It would be interesting to see if this also applies to the treatment of migraine headaches.

Art credit: JulieMauskop.com

Vagus nerve stimulation (VNS) seems to be effective for the treatment of migraine headaches. In my post over a year ago I mentioned our study of a device that stimulates vagus nerve with an external portable device. The results of this study were just presented at the annual scientific meeting of the American Academy of Neurology. The device was developed by scientists at ElectroCore, a small company following my publication of a study of implantable VNS in 6 patients. In the current study we included patients with migraine with or without aura. Participants acutely treated up to 4 migraine attacks with this portable VNS within 6 weeks. Treatment consisted of two, 90-second doses, at 15-minute intervals. Patients were asked to self-treat once pain became moderate or severe, or after 20 minutes of mild pain. Of 30 enrolled patients, 26 treated 79 migraine headaches. At two hours, 46 of 79 headaches (58%) responded, and in 22 out of 79 (28%) pain was completely gone. At two hours, 76 of 79 (96%) were improved or did not worsen. Of 26 patients 20 (77%) reported mild or nor pain at 2 hours, for at least one treated headache. Side effects were limited to muscle or skin irritation and two reports of lightheadedness, most of which resolved immediately after treatment, and all within two hours of treatment. These are very preliminary results, but they suggest that VNS may be an effective and well-tolerated acute treatment for migraine. Additional large clinical trials are needed to confirm these findings.

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A recently published study by neurologists at the Military Medical Center in San Antonio led by Dr. Grogan tried to find predictors of response to botulinum toxin injections in chronic migraine sufferers. They looked at the records of 128 patients who received injections of botulinum toxin, although they did not receive Botox (onabotulinumtoxinA), but a similar product, Myobloc (rimabotulinumtoxinB). It has been previously reported (and mentioned in this blog) that patients with headaches who experience constricting pain or pain in the eye are more likely to respond than those who have an “exploding” headache or pain with pressure felt going from inside out. This new study confirmed this observation, originally made by Dr. Rami Burstein and his colleagues at Harvard Medical School. Dr. Grogan and his colleagues’ patients received an average of 7 and a half treatments over a period of 22 months. Treatment results showed that 80% of their patients who received injections of Myobloc had at least a 50% improvement and 57% had a greater than 75% reduction in their headache frequency. This is similar to the 70% response rate we see with Botox injections. Patients who had migraine with aura were more likely to respond to Myobloc injections. Just like with Botox side effects were few and mild and only 4% of patients decided to stop this treatment due to side effects. More patients who received Myobloc (82%) complained of pain during injections. I have also observed this and the reason is that Myobloc is very acidic, while Botox is non-acidic.
There are two other botulinum toxin products on the market, but only Botox is approved by the FDA for the treatment of chronic migraine headaches. These other two products are Dysport (abobotulinumtoxinA) and Xeomin (incobotulinumtoxinA) and they are more similar to Botox than Myobloc because they are also type A botulinum toxins, while Myobloc is type B. Only Botox is approved by the FDA for the treatment of chronic migraine headaches, while the other three are approved for movement disorders such as dystonia as well as for cosmetic use.

A typical visual aura which precedes the headache in about 20% of migraine sufferers usually lasts 20 to 60 minutes. A small number of patients suffer prolonged auras, which can last for hours. While we have many medications to treat the pain of migraine, we have no effective way to stop a prolonged aura. The only possible exception is intravenous magnesium, which I have found to help some patients for prolonged visual and other types of aura. Researchers at UCSF led by Dr. Peter Goadsby conducted a rigorous blinded study of intranasal ketamine for prolonged auras. They compared ketamine to a strong tranquilizer, midazolam. The results of the study published in Neurology showed that ketamine but not midazolam can make aura milder, but it did not shorten it. Ketamine is a drug given intravenously for anesthesia, but it has been also widely tested for the treatment of pain, albeit with mixed results.

I failed to mention in my two previous posts that there is a difference in the type of electrical current used in transcutaneous electrical nerve stimulation (TENS) and transcranial direct current stimulation. The former uses alternating current, while the latter is a direct current (AC vs DC). Cefaly device uses AC, while tDCS devices use DC. It is possible that both types of stimulation are equally effective for chronic migraine headaches and other conditions. We would need to have a blinded trial comparing these two types of stimulation to see if one is superior to the other.

An article in today’s New York Times reported on the efficacy of electrical brain stimulation for the treatment of depression. It described a study published last week in the journal JAMA Psychiatry, in which a commonly used antidepressant, sertraline (Zoloft) was compared with transcranial direct current stimulation, or tDCS. This blinded study showed that Zoloft and the electrical stimulation of the brain were equally effective, but the electrical stimulation lacked the side effects of the drug. Combining electrical stimulation with Zoloft produced even better results. This type of electrical stimulation is very safe and is somewhat similar to the transcutaneous electrical stimulation mentioned in my previous post. tDCS was also tried in patients with chronic migraines. A study published in Headache last year showed that pain intensity and migraine duration was reduced after 10 sessions of tDCS given over a period of 4 weeks. Even though the study involved only 13 patients, the active treatment was compared to sham stimulation, which makes the findings more likely to be true, rather than due to the placebo effect. It is too early to recommend tDCS for the treatment of chronic migraines. However, this is a very safe and inexpensive treatment that may be worth trying before other unproven, more expensive, and more invasive treatments, such as occipital or supraorbital nerve stimulation or migraine surgery.

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Electrical stimulation of the nervous system is widely used for a variety of conditions and in a variety of ways. The nervous system can be electrically stimulated at the level of the brain, by implanting electrodes into the brain, at the level of spinal cord, also with implanted electrodes or at the level of peripheral nerves in the skin by attaching an adhesive electrode or with an implanted wires. The conditions that can be helped by electrical stimulation range from Parkinsons disease and depression to chronic low back pain and post-herpetic neuralgia (shingles). Stimulation of the nerves through adhesive electrodes temporarily attached to the skin is called transcutaneous electrical stimulation, or TENS. TENS has been proven to help a variety of musculo-skeletal conditions, such as back pain and arthritis pain.
There have been some studies of the use of TENS for headaches, but none of them have been as rigorous and scientific as the one just published in Neurology. The lead author, a Belgian neurologist and a headache specialist Dr. Jean Schoenen and his colleagues conducted a study on 67 patients with a proprietary TENS device called Cefaly. The device is put on the forehead like eyeglasses and it contains electrodes which stimulate the nerves above the eyes. The study showed that by using this stimulator for 20 minutes daily for 3 months patients reduced the number of their migraine headaches from an average of 7 to 5 a month. Those patients who put on the device but were not given electrical stimulation (the sham, or placebo group) did not improve.
The device costs about $368 on Amazon and $240 at Costco in Canada. It is not clear if this device offers any advantages over a TENS unit that costs about $50 and is widely available in this country. Perhaps, Cefaly is much more convenient in that it does not require adhesive electrodes with wires attached to a little box. Another possible advantage is the stimulating current may have specific frequency, strength and wave shape, which provides better relief. However, an electrical engineer could easily hook up the Cefaly unit to a monitor and figure out and publicize these settings. I do not suggest that the people who developed this device and did all the testing do not deserve to be financially rewarded. They may, in fact be rewarded because their device is significantly more convenient and simple to use and many people will prefer it to a more cumbersome device.

Photo credit: Cefaly.com