The introduction of Levadex has been delayed again, this time for a year. It seems like deja vu all over again – I wrote the same thing on this blog in April of last year. Levadex, which the manufacturer (Allergan) just renamed as Semprana, is an inhaler containing DHE. DHE, or dihydroergotamine is one of the most effective injectable drugs for migraine. It should be even better in an inhaled form because it works faster and causes much less nausea than the injection. The FDA is again delaying the launch because of manufacturing problems. Apparently, the particle size of the drug when it comes out of the inhaler is not uniform enough. Many patients are unhappy, but I am sure that the Allergan is very unhappy too since they spent almost a billion dollars to acquire this drug from a small company that developed it.

Two new migraine drugs are about to be released on the market. They were mentioned in this blog in their earlier stages of development. Another two drugs are more interesting, but are several years away from becoming available (if at all).

Zecuity is a patch that delivers sumatriptan (active ingredient in Imitrex) through the skin. The patch contains a small battery and the electric current it generates helps the medicine penetrate through the skin. The patch is particularly useful when migraine is accompanied by nausea and vomiting. The main side effect of the patch, compared to the tablet, is that it causes irritation of the skin in one third of patients. This product was already approved by the FDA and will be soon available in pharmacies from its manufacturer, Teva Pharmaceuticals.

Levadex is a drug inhaled into the lungs using a device similar to those used for asthma drugs. It contains dihydroergotamine – a very old and very effective injectable drug. Dihydroergotamine does not work well in a nasal spray (Migranal) or when taken by mouth. Levadex causes less side effects, such as nausea, than the injection of this drug. The main target population for this drug is also migraine sufferers who experience nausea and vomiting and for whom tablets do not work. Because it works very fast it may be also very effective for those whose headache starts and escalates to a severe intensity very quickly, which includes not only migraine, but also cluster headache sufferers. Levadex is manufactured by Allergan, the company that also makes Botox. It should be available in the next few months.

Lasmitidan is a new drug being developed by CoLucid. It is in phase III trials, which is the final phase, which if successful, can lead to the FDA approval. Lasmitidan is a new type of drug – it targets a specific serotonin receptor subtype – 1F, while triptans (sumatriptan, rizatriptan, and other) target 1B and 1D serotonin receptors. It may have the advantage of not constricting arteries at all and may be allowed in patients with coronary artery disease. Triptans are contraidicated in such patients.

Merck is developing a drug, which does not have a name yet, only a number – MK-1602. It is a CGRP receptor antagonist – a blocker of a neurotransmitter in the brain that is involved in migraine origination. It is in phase II trials. MK-1602 also has the advantage of not constricting arteries. At least two other companies are developing CGRP antibodies (different from CGRP antagonists) and they were mentioned in a recent post here.

The versatility of botulinum toxin continues to amaze. The use of botulinum toxin (Botox) for the treatment of migraine headaches (pioneered at the New York Headache Center) is becoming widespread in the US. The original FDA-approved indications for botulinum toxin was a rare eye condition, blepharospasm as well as strabismus. The number of indications (not all of them yet FDA-approved) for botulinum toxin has increased very quickly – from cosmetic use for wrinkles to gastrointestinal disorders (narrowing of the esophagus, rectal fissures), excessive sweating, muscle spasticity of cerebral palsy and following a stroke, neuropathic pain (neuropathy, trigeminal neuralgia, shingles), spastic bladder (which causes frequent urination), and other.

Injecting botulinum toxin into the fat pads around the heart after coronary bypass surgery seems to reduce the incidence of atrial fibrillation, an irregular hear beat. This is the conclusion of a randomized and blinded study of 60 patients, half of whom were injected with saline water and the other half with botulinum toxin (not Botox, but one of the other 3 botulinum toxin products, Xeomin).

Patients who received injections of botulinum toxin instead of saline water had a significantly lower rate of irregular heart beats in the first 30 days (30% versus 7%), according to Evgeny Pokushalov, MD, PhD, of the State Research Institute of Circulation Pathology in Novosibirsk, Russia. Injections of botulinum toxin around the heart did not cause any complications or side effects. These irregularities of heart rhythm can be dangerous and if these findings are confirmed, botulinum toxin injections may become standard during coronary bypass surgery. If these injections are indeed effective they would also save money by reducing the duration of hospital stay and preventing the need for additional treatments of irregular heart beat.

Antibodies blocking a specific neurotransmitter involved in migraines appear to relieve migraine headaches. Two studies presented at the annual meeting of the American Academy of Neurology reported on the use of antibodies to CGRP (calcitonin gene-related peptide) for the treatment of migraine headaches. These were relatively small, but highly scientific (randomized, double-blind, and placebo-controlled) studies. The studies was conducted in patients with frequent migraines.

The two studies used two different antibodies developed by different companies. The results of the trials suggest that this approach is both effective and safe in preventing migraine, at least according to these preliminary studies.

If these antibodies are proven to be indeed safe and effective, they will be the first specific migraine therapy since the introduction of triptans over 20 years ago. Triptans (sumatriptan and other) are abortive drugs, meaning that abort a migraine attack, while CGRP antibodies are used for the preventive (prophylactic) treatment. While Botox was approved three years ago for the preventive treatment of chronic migraines it was not specifically developed for the treatment of migraines. Instead, Botox was found to have this effect accidentally.

One phase II proof-of-concept trial enrolled 218 people with 4 to 14 migraine headache days per month and randomly assigned them to get the antibody or a placebo. The study medication was given every 2 weeks by subcutaneous injection. Active treatment resulted in reduction of an average of 4.2 migraine days per month in the third month for those on the active drug and a drop of 3.0 days for those on placebo.

The side effects were similar between the groups and most were mild and resolved on their own.

In the other study the antibody was given intravenously at the start of the trial, with an hour-long infusion, but was not repeated. This study enrolled 163 patients, with 82 assigned to the drug and 81 to placebo. The average change from baseline in migraine days per month was a decline of 5.6 for the active treatment compared with a drop of 4.6 for placebo patients. Side effects in this study were also mild and occurred with the same frequency in the active and placebo groups.

While the difference between the active treatment and placebo does not seem to be significant, it was statistically significant and it is possible that some patients will respond very well while others not at all.

The next step is much larger phase III studies, which typically involve over 1,000 patients for each compound. If phase III studies also show safety and efficacy of these antibodies, then the FDA might approve them. This means that the earliest one or both of these drugs will become available is about 3 years.

The companies that sponsored these studies were Arteaus and Alder Biopharmaceuticals.

An oral tablet is the most convenient way to take medicine. However, many migraine sufferers wake up with a headache that is in full bloom and severe nausea or vomiting makes it difficult to take oral medications. Others find that tablets are ineffective or take too long to work.

Sumatriptan (Imitrex), the miracle migraine drug which has changed lives of millions of migraine and cluster headache sufferers, was first released in an injection. The injection is still available and is the most effective way to stop a migraine. The injection comes in a variety of pre-filled syringes and cartridges, which are very easy to self-inject. The problem with injections is that some people don’t like the idea of injecting themselves, which is surprising, considering how much pain and suffering they endure from migraine. Another problem is the cost – even in a generic form a shot costs $35 (see GoodRx.com for cheapest prices). The biggest reason why injections are underutilized is that doctors fail to offer this option to patients, many of whom would be happy to use it.

Nasal sprays offer a middle ground option – not as fast or effective as an injection, but faster and sometimes more effective than a tablet. There are several medications available in a nasal spray. The same triptan medication, sumatriptan comes in a nasal spray. However, another triptan, zolmitriptan (Zomig NS) in my experience is more effective. The disadvantage of Zomig is that it is very expensive if not covered by insurance (over $200 a spray) because it is not available in a generic form.

Another nasal spray approved for migraine headaches is Migranal. It contains dihydroergotamine, which is one of the strongest injectable migraine drugs. However, it is much less effective in a nasal spray form. It is also very expensive – $200 a dose. Dihydroergotamine is about to be released in an inhaler. It will be called Levadex and will deliver the medicine into the lungs. Its efficacy should be as good as that of an injection, but with fewer side effects. Hopefully, it will not be more expensive than the generic sumatriptan injection. Otherwise, just like with Migranal, insurance companies will not cover it.

Sprix is a nasal spray containing ketorolac. In a tablet form (Toradol) ketorolac is no more effective than aspirin and is more irritating to the stomach. But it is a very effective drug for migraines when it is injected and to a lesser extent, when sprayed into the nose. It is very popular as an injection in the ERs and at our New York Headache Center. Sprix can sometimes irritate the nasal passages. It costs about $35 a dose.

Stadol (butorphanol) is a narcotic (opioid) pain killer, which costs about $30 a dose in a generic form. It does relieve pain well and is approved for migraine headaches. However, just like other narcotics, it is potentially addictive. Also, many migraine sufferers find that narcotics do not help their migraine and often makes them feel sicker. It also costs over $30 a dose.

There are several over-the-counter nasal sprays containing hot pepper extract, capsaicin. There is no good scientific evidence that these capsaicin products sprayed into the nose relieve migraines or cluster headaches. On the other hand, besides burning and irritation of the nasal passages, they have few side effects and are inexpensive.