Dihydroergotamine (DHE-45) when given intravenously (IV) is considered to be the most effective migraine medication. It was introduced in 1943 and has been the go-to drug for migraines that do not respond to other medications. We usually consider using dihydroergotamine (DHE) after the failure of oral triptans, nonsteroidal antiinflammatory and steroid drugs, as well as injections of ketorolac (Toradol), sumatriptan (Imitrex), and metoclopramide (Reglan), and in some patients, nerve blocks.

Raskin protocol, named after Neil Raskin who still practices headache medicine in San Francisco, calls for IV DHE with metoclopramide to be given every 8 hours to break a persistent migraine attack that does not respond to other measures.

The Raskin protocol is typically administered in a hospital. However, if the patient is able to, we sometimes have her come in for an infusion in the morning and a second time in the late afternoon. DHE often worsens nausea and we usually pretreat patients with ondansetron (Zofran) or metoclopramide. A minority of patients do not experience nausea with their migraines and they usually do not develop it with dihydroergotamine.

A few of our patients self-administer this drug subcutaneously at home. Subcutaneous injection is not as effective as when the drug is given intravenously, but for some patients it works very well. Some take an oral nausea medication or even self-inject a nausea drug prior to giving themselves an injection of DHE. DHE is available only in glass vials and it is prescribed with a syringe.

Dihydroergotamine nasal spray (Migranal) has been available for over a decade and its approval was based on a double-blind trial in 348 patients. The results of this trial are impressive, but in clinical practice I do not find it to be highly effective.

Headache specialists were very excited with the results of studies showing that inhaling DHE into the lungs provides excellent and consistent relief with few side effects. The FDA had accepted the safety and the efficacy data, effectively approving the drug (to be called Levadex and then, Semprana). However the FDA had found manufacturing inconsistencies. The small company that developed inhaled DHE, MAP Pharmaceuticals was acquired by Allergan (for close to a billion dollars). Unfortunately, after five years of failed efforts it seems that Allergan has given up on trying to fix the production problem.

Diclofenac (Cambia, Voltaren) is one of the nonsteroidal anti-inflammatory drugs (NSAIDs) used for the treatment of migraine headaches. Cambia, which contains 50 mg of powdered diclofenac, is specifically approved by the FDA for the treatment of migraine headaches. It works faster because the powder gets dissolved in a glass of water and the solution of diclofenac (or any other drug) gets absorbed faster than a solid pill. Cambia has a licorice taste, so if you are born disliking licorice (yes, it is an inherited trait), this drug is not for you. It is also not for you if your insurance refuses to pay for it – the out-of-pocket cost is $70 to $80 for a single a dose, or $630 to $740 for a box of 9 packets.

The insurers rightfully want you to first try generic diclofenac in a tablet form, which costs $0.30 a pill. Drinking a full glass of water will speed up the dissolution of the tablet and in some patients could potentially match the efficacy of Cambia.

Taking diclofenac in any formulation on an empty stomach makes it work faster, but may increase the risk of heartburn and peptic ulcers. All NSAIDs taken very frequently can increase the risk of heart attacks and strokes in people with cardiovascular risk factors. However, some NSAIDs are worse than other and diclofenac is one of the worst ones while naproxen is one of the safest ones.

I mention this on every suitable occasion – NSAIDs have not been proven to cause rebound or medication overuse headaches (MOH). In fact, daily intake of naproxen was proven to be an effective strategy for the prevention of migraines. MOH has been only proven to occur from a frequent intake caffeine and opioid (narcotic) pain killers.

Dichloralphenazone is one of three ingredients in the headache drug, Midrin. The other two ingredients are isometheptene, a drug that constricts blood vessels and acetaminophen. Midrin actually is a combination of four drugs because dichloralphenazone is broken down in the body into chloral hydrate, which is an old sedative hypnotic drug used for insomnia and antipyrine, a non-steroidal anti-inflammatory pain medicine.

Midrin is a very old drug which was introduced before the 1962 Congressional act that required rigorous clinical trials for the FDA approval. It has been marketed for both migraine and tension-type headaches. The directions, which are not based on any research studies, recommend: “For relief of migraine headaches: The usual adult dosage is two capsules at once, followed by one capsule every hour until relieved, up to 5 capsules within a twelve hour period. For relief of tension headache: The usual adult dosage is one or two capsules every four hours up to 8 capsules a day.”

Several small studies of Midrin have been published. One double-blind study, published in 1976 involved 43 patients who were rotated from Midrin to acetaminophen and then, placebo. Midrin was found to be more effective. Another double-blind study, published in 2001 compared Midrin with sumatriptan (Imitrex), 100 mg and found them to be equally effective.

I do come across an occasional patient for whom Midrin is more effective than the triptans or any other drug without causing any side effects. Or, sometimes the side effect of sedation is preferable to having a migraine that does not respond to any medication.

Because Midrin contains a sedative medications, which is potentially addictive, it is considered to be a controlled drug. The supply of Midrin has been very inconsistent because it lacks an official FDA approval and because very few doctors prescribe it. When it is not available from a pharmaceutical manufacturer some doctors order it from a compounding pharmacy, which makes Midrin by mixing the three individual ingredients by hand in small batches.

Desvenlafaxine (Pristiq) is an antidepressant in the family of serotonin and norepinephrine reuptake inhibitors (SNRIs). Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac) and escitalopram (Lexapro) are more popular for the treatment of depression and anxiety, but they are less effective than SNRIs for the prevention of migraines and the treatment of pain. Venlafaxine (Effexor) was the first drug in the class of SNRIs, but at the doses below 150 mg works as an SSRI, inhibiting only the reuptake of serotonin. At 150 mg it begins to inhibit the reuptake of norepinephrine, which is responsible for pain relief.

Venlafaxine is broken down in the body into an active metabolite, desvenlafaxine. So desvenlafaxine can be considered a purified form of venlafaxine. The FDA approved recommended starting and maintenance dose for desvenlafaxine is 50 mg daily and this dose produces the dual effect, while venlafaxine requires titration from 37.5 mg daily to the maintenance dose of 150 – 300 mg daily. Potential side effects of desvenlafaxine include increased or excessive sweating, dizziness, drowsiness, dry mouth, constipation, insomnia, and loss of appetite.

While venlafaxine has been shown to prevent migraine headaches, such research is lacking for desvenlafaxine. However, considering that two other SNRI drugs, duloxetine (Cymbalta) and milnacipran (Savella) are FDA-approved for pain, it is very likely that desvenlafaxine can also help prevent migraines and relieve other types of pain.

Desipramine (Norpramin) belongs to the family of tricyclic antidepressants which have been proven to be effective for the treatment of various pain syndromes and for the prevention of migraine headaches. Desipramine is used much less frequently for migraines than amitriptyline (Elavil) or nortriptyline (Pamelor) and there are no controlled trials of this drug for the prevention of migraines. However, it has been proven to be as effective in relieving pain of diabetic neuropathy as amitriptyline. It was also shown to be effective for the treatment of postherpetic neuralgia (shingles pain) and chronic low back pain.

Desipramine has the advantage of being less sedating than the more popular tricyclic antidepressants and causing fewer other side effects, such as dry mouth and constipation. In one study desipramine caused less weight gain than amitriptyline (but as much as nortriptyline). It is dosed similarly – it is started with 10 or 25 mg and the dose is gradually increased as needed and as tolerated. The average dose for the treatment of pain is between 25 and 75 mg, while for depression it can go up to 150 mg.

All tricyclic antidepressants can cause cardiac arrhythmias, especially at high doses and an electrocardiogram is indicated in those with heart disease or multiple risk factors for heart disease. We tend to avoid it in the elderly also because of the increase in the risk of falls due to sedation, as well as constipation. Tricyclics can lower seizure threshold and should be avoided in people with epilepsy.

Celecoxib (Celebrex) is a non-steroidal anti-inflammatory drug (NSAID) that belongs to a subclass of selective COX-2 inhibitors. This subclass of drugs tends to be safer on the stomach compared to aspirin, naproxen (Aleve), ibuprofen (Advil) and other non-selective NSAIDs.

400 mg of Celecoxib was shown to be as effective as 550 mg of naproxen for the acute treatment of migraine headaches. A course of celecoxib was also shown to be better than a course of prednisone for the treatment of medication overuse headaches. Celecoxib is a prescription drug and even though it is available as a generic, it costs $3-$4 a pill, but many insurers do pay for it.

Another selective COX-2 inhibitor, rofecoxib (Vioxx) was possibly even more effective than celecoxib for the acute treatment of migraines. However, its long-term use for arthritis in those with heart disease or risk factors for heart disease was found to contribute to heart disease and heart attacks and it was taken off the market. This was very unfortunate because migraine patients tend to be young without risk factors for heart disease and they tended to use rofecoxib only occasionally. Such use was perfectly safe and certainly safer than the use of naproxen, ibuprofen, diclofenac, and other NSAIDs.

Valdecoxib (Bextra) was another COX-2 inhibitor taken off the market.