Duloxetine (Cymbalta) is an antidepressant in the family of serotonin-norepinephrine reuptake inhibitors (SNRIs). Unlike the selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac), escitalopram (Lexapro) and other, SNRIs not only treat depression and anxiety, but also relieve pain and prevent migraine headaches.

Duloxetine is specifically approved by the FDA for the treatment of major depression, generalized anxiety, musculoskeletal pain, such as low back pain and pain due to osteoarthritis, as well as pain of fibromyalgia and diabetic peripheral neuropathy.

Duloxetine is not officially approved for the treatment of migraine headaches, but it is been widely for this indication. There are no large controlled trials, but several small studies show that it may be effective even for chronic migraines with medication overuse. Most studies employed a dose of 60 mg, but one study suggested that high doses of the drug (120 mg) may be more effective for the prevention of episodic migraine headaches.

Considering that duloxetine is proven to relieve pain of different types, it is very likely that it is effective for the prevention of migraines as well. It is particularly a good choice in patients with comorbid anxiety and depression and these conditions are 2-3 times more likely to occur in migraine sufferers.

Potential side effects include insomnia, drowsiness, fatigue, nausea, dizziness, suicidal thoughts in depressed children and young adults, and other

Sudden discontinuation of duloxetine can cause withdrawal symptoms, which may consist of one or more of the following symptoms: dizziness, headache, nausea, diarrhea, paresthesia (pins-and-needles), irritability, vomiting, insomnia, anxiety, sweating, and fatigue. These can be avoided by a very gradual reduction in the dose. On occasion, when the dose is down to the smallest size capsule of 20 mg, stopping it can cause withdrawal symptoms. In such cases I advise the patient to open the capsule and to discard ever increasing amounts of the drug for a period of a week or two.

Droperidol (Inapsine) is not a phenothiazine, but is structurally very similar to this class of anti-nausea and anti-psychotic drugs. It also has similar properties of relieving nausea and being a major tranquilizer. And just like phenothiazines (prochlorperazine or Compazine, chlorpromazine or Thorazine, and other) it helps relieve migraines.

An intravenous infusion of droperidol stopped a very severe and prolonged migraine that failed to respond to other treatments in 30 out of 35 patients. Most of them became drowsy from the drug and 5 developed severe restlessness and involuntary movements (akathisia).

Intravenous and intramuscular droperidol has been shown to be more effective than prochlorperazine in an emergency room setting, but it had more side effects. Akathisia and sedation were present in 15% of patients.

A randomized, double-blind, placebo-controlled trial of droperidol injected intramuscularly involving over 300 patients showed its efficacy in treating migraines. However, droperidol produced the same problematic side effects as all phenothiazines can. In this trial 30% of patients had anxiety, akathisia (restlessness and inability to stay still), and somnolence that was rated as severe. Intravenous diphenhydramine (Benadryl) can help reduce these side effects. Another potentially serious side effect is irregular heart beat, or cardiac arrhythmia, which can be life-threatening.

Over the years I’ve given droperidol on a rare occasion in the office without few side effects and with good relief. However, because of the potential for serious side effects I no longer administer it. Fortunately, we have many other intravenous drugs to stop a severe persistent migraine – magnesium, ketorolac (Toradol), dihydroergotamine (DHE-45), ondansetron (Zofran), metoclopramide (Reglan), dexamethasone (Decadron), valproic acid (Depakene), and other.

Doxepin (Sinequan) is a tricyclic antidepressant and all drugs in this category (amitriptyline, nortriptyline, desipramine, protriptyline) appear to be effective for the prevention of migraine headaches.

Only a single small trial of doxepin was conducted in patients with chronic migraines. However, it is very likely that it is as effective as other antidepressants. Doxepin is one of the more sedating tricyclics and is more often used for insomnia than depression or migraines. A typical starting dose of doxepin is 10 mg. The dose is increased to 25-75 mg for migraines and up to 150 mg for depression. For sleep, even 3 or 6 mg dose can be sufficient and such doses in a branded product, Silenor are approved by the FDA for insomnia. Branded products are usually very expensive and Silenor is no exception – $15 a pill, while 10 mg of doxepin is $.50.

Side effects of doxepin are similar to those with other tricyclics – daytime drowsiness, even if taken only at night, dizziness, dry mouth, constipation, weight gain, and other. These side effects is what limits the usefulness of this category of effective migraine drugs.

Domperidone (Motilium) is not a champagne (that would be Dom Perignon and it can give you a headache) but an excellent nausea medication which is often used for the treatment of nausea associated with migraines. It is available in 58 countries but unfortunately not in the US. In desperate cases I’ve had some patients get it from Canada or Europe.

Domperidone works in a different way from other nausea medications and can be effective when other drugs are not. Besides being good at relieving nausea, one study suggested that it can prevent migraine attacks if taken in the prodrome period, 6 to 12 hours before the attack. Prodrome is a prelude to a migraine attack and it can consist of one or more of the following symptoms: fatigue, elation, irritability, depression, yawning, increased urination, food cravings, and other. Not every person has a prodrome, although some people are just not aware of the warning symptoms which can occur a day or two before the attack.

Domperidone was also shown to shorten migraine attacks when taken with paracetamol (acetaminophen, or Tylenol in the US). This combination of domperidone with paracetamol (Domperamol) is as effective as 50 mg of sumatriptan (Imitrex, Imigran).

A study comparing domperidone with metoclopramide (Reglan), a drug very popular in the US showed that they are equally effective for nausea in diabetics with gastric motility problems, but domperidone had fewer neurological side effects. These neurological side effects included drowsiness, reduced mental acuity, restlessness, fatigue, and depression. Very rarely, metoclopramide, prochlorperazine (Compazine), and similar drugs can lead to a devastating side effect – persistent involuntary movements of the face and other parts of the body.

Domperidone has very few side effects, but should be used with caution in older patients because it can cause serious cardiac arrhythmias.

Divalproex sodium (Depakote) is one of two epilepsy drugs that are also approved by the FDA for the preventive treatment of migraine headaches (the other one is topiramate, or Topamax). It was approved by the FDA in 1983 to treat epilepsy, in 1985 it was also approved to treat bipolar disorder, and in 1986, to treat migraines.

Divalproex is very effective in about 50% of migraine sufferers. The starting dose is 500 mg of the extended release form (Depakote ER). Some patients require 1,000 mg and in epilepsy patients, up to 2,000 and even more, depending on the blood level of the drug. Potential side effects include nausea, drowsiness, dizziness, hand tremor, and in about 10% of patients, weight gain and hair loss. These side effects can be quite unpleasant, but unfortunately, much more serious side effects can occur as well. These are rare, but when they occur, they can be devastating.

The drug carries a so called black box warning. It in includes hepatotoxicity, or liver damage, which can be fatal. It usually occurs during the first 6 months of treatment and the FDA label calls for monitoring patients closely and regularly performing blood tests. Fatal cases of pancreatitis have been also reported. Another major problem with this drug is birth defects if taken by the mother during pregnancy. Considering that the majority of migraine sufferers are women of child-bearing age and because of all other potential side effects I rarely prescribe divalproex.

It is appropriate to try divalproex after the patient fails to respond to a variety of other treatments, including blood pressure medications, antidepressants, Botox injections, and the new category of CGRP monoclonal antibodies (Aimovig, Ajovy, and Emgality). The patient must be informed of the potential side effects listed above and sexually active women of child-bearing age should be advised to use two methods of contraception.

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.