Dihydroergotamine (DHE-45) is a very old migraine drug in the family of ergot alkaloids. It is one of the most effective migraine drugs when it is given intravenously and it is often used when patients are admitted to the hospital for migraines that do not respond to other therapies.

Dihydroergotamine (DHE) is also available as a nasal spray (Migranal), but it works well only in a limited number of patients and is very expensive. This poor consistency of effect is partly due to the amount of liquid that needs to be sprayed for one dose, most of which is either swallowed or leaks out. A form of DHE to be inhaled into the lungs had been in development for many years, but is not likely to become available due to manufacturing difficulties.

A promising new way to deliver DHE as a nasal powder is being developed by Satsuma Pharmaceuticals. The company presented their preliminary data at the recently concluded scientific meeting of the American Headache Society in Philadelphia. Their study showed that powdered form of DHE delivered into the nose gets into the blood faster and better than the existing nasal liquid form, although not as well as when it is given as an intramuscular injection. The device to administer DHE is small and easy to use, unlike another device that is also being developed for intranasal delivery of DHE powder. The company is initiating a large clinical trial, which will hopefully lead to the approval of their product.

Ketamine (Ketalar) was officially approved for human use by Food and Drug Administration (FDA) in 1970 and, because of its wide margin of safety, was even administered as a field anaesthetic to soldiers during the Vietnam war. Concerns over the psychedelic effects of ketamine and the arrival of new intravenous hypnotics such as propofol led to a marked decrease in the use of ketamine for anesthesia, but in the recent years its use has been increasing. Its unique properties have led many researchers to do clinical trials for the treatment of pain and depression. Intranasal ketamine was just approved by the FDA for treatment-resistant depression.

True efficacy of ketamine for the treatment of pain and migraine headaches is less clear. There have been no double-blind studies of ketamine for the treatment of migraine headaches. A major obstacle to doing such studies is that it is very difficult to blind patients to the effect of ketamine. We do have anecdotal evidence, that is a description of series of patients who were given intravenous ketamine. A report entitled, Ketamine Infusions for Treatment Refractory Headache describes 77 chronic migraine patients who “failed aggressive outpatient and inpatient treatments”. These patients were hospitalized and were receiving ketamine infusions for an average of 5 days. Over 70% of these patients improved, although only 27% had sustained improvement.

In a report published in The Journal of Headache and Pain authors describe 6 patients admitted to the hospital whose refractory migraines improved with intravenous ketamine, albeit the improvement was only short-term. One patient reported a transient out-of-body hallucination, which resolved after decreasing the rate of infusion.

Intranasal ketamine was shown to relieve severe migraine aura in 5 of 11 patients with familial hemiplegic migraine. In some patients, the aura can be more debilitating than the headache or other symptoms of migraine and we have no effective treatment to stop the aura once it stops.

A Randomized Controlled Trial of Intranasal Ketamine in Migraine With Prolonged Aura, was a study of 18 patients published in Neurology. It showed that intranasal ketamine reduces the severity but not the duration of migraine aura.

I have referred a small number of patients whose migraines fail to respond to a wide variety of treatments for outpatient intravenous ketamine infusions. A few of these patients found ketamine to be very helpful. This is not a fair test of the drug’s efficacy because those who failed to respond to 20 different treatments are not likely to respond to the 21st one. Considering that ketamine is fairly safe (the dose given is much smaller than the dose used for anesthesia), it would be useful to have a controlled randomized trial in less refractory patients.

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