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.

Bisoprolol (Zebeta) is one of about a dozen drugs in the beta-blocker family, medications that were developed for the treatment of high blood pressure, or hypertension. The oldest beta blocker, propranolol (Inderal) was approved by the FDA for the treatment of hypertension about 60 years ago and a decade later it was also approved for the prevention of migraine headaches. Timolol (Blocadren) is the only other beta blocker that is officially approved for migraines, but most likely they all work. Even though they are very similar, beta blockers may have different efficacy and especially, different side effects from patient to patient. A drug that works well and without side effects in one person may cause side effects in the next. Also, not all beta blockers have been subjected to rigorous double-blind trials for the prevention of migraines, so we tend to prescribe the ones that do have some evidence supporting their efficacy in migraines.

Bisoprolol is one of the beta blockers that has scientific evidence suporting its use in migraines. A blinded study comparing bisoprolol, 5 mg with metoprolol (Lopressor, Toprol), 100 mg, another beta blocker showed them to be equally effective in the treatment of migraines.

The European Federation of Neurological Societies recommends bisoprolol as a second-line beta blocker for the prophylactic treatment of migraine headaches, after propranolol and metoprolol. THe US guidelines list bisoprolol further down the list.

Fremanezumab (Ajovy) was just approved by the FDA for the preventive treatment of migraine headaches. It is the second drug, following erenumab (Aimovig), with a similar mechanism of action. While erenumab blocks calcitonin gene-related peptide (CGRP) receptor, fremanezumab binds to the CGRP molecule and blocks its attachment to the CGRP receptor. Both are very effective in preventing migraine attacks and both, so far, appear to be very safe. Just like erenumab, it is approved for the prevention of migraines without regard to the frequency of attacks, unlike onabotulinumtoxinA (Botox), which is only approved for chronic migraines, which are defined as occurring on 15 or more days each month.

Here are some differences between the two drugs that we know of so far. Fremanezumab can be injected monthly or with a triple dose, every three months. Considering that one of my patients developed a rash from erenumab (no surprise there – any drug can cause an allergic reaction), I probably will start with a single shot once a month and then may give a triple dose every three months. The second difference is that constipation is not listed as a side effect of fremanezumab in the FDA-approved prescribing information, while it is listed as occurring in 3% of patients on erenumab. Since these drugs have a similar mode of action, I will not be surprised if fremanezumab also causes constipation in some patients. So far, only two of my patients (out of about 300) declined to continue erenumab because of constipation.

Erenumab is available only in an easy-to-use autoinjector pen, while fremanezumab comes only in a prefilled syringe. I suspect some patients will prefer to come into the office every three months to get their fremanezumab injections, rather than inject themselves, but the majority will self-inject it. One advantage of prefilled syringes is that a small test dose can be given before giving the entire amount. This is what I plan to do for my patient who developed a rash from erenumab.

Bupivacaine (Marcaine, Sensorcaine) is a numbing agent (local anesthetic) similar to lidocaine (Xylocaine), but with a longer duration of effect. Bupivacaine effect lasts 4 to 8 hours, while lidocaine, only 2 hours. However, lidocaine begins to work in 2 to 5 minutes, while bupivacaine takes 5 to 10 minutes.

We use bupivacaine to treat migraines in two ways. One is in combination with lidocaine to perform nerve blocks. Nerve blocks can be very effective in stopping a stubborn migraine that does not respond to medications such as triptans, NSAIDs, intravenous magnesium, ketorolac, and other. We also give nerve blocks to pregnant women who fail to respond to intravenous magnesium and before using systemic drugs, that is drugs taken by mouth or by injection and that are distributed throughout the body, including the fetus.

The nerve blocks are done with small needles, although during a migraine attack even a small needle can be painful. However, relief from the numbing effect of lidocaine comes within minutes, while bupivacaine in the mixture provides longer lasting relief. Some headache specialists give regular nerve blocks every 3 months in place of onabotulinumtoxinA (Botox) injections. Nerve blocks are not as effective as Botox, but we do give nerve blocks when the effect of Botox wears off sooner than 3 months. Ideally, we try to give Botox earlier, but many insurance companies will not allow Botox injections more often than every 3 months.

We also use bupivacaine by itself for sphenopalatine ganglion (SPG) blocks . These blocks are not painful since they are done without a needle. Bupivacaine is delivered to the ganglion which is located behind the nasal cavity and underneath the brain through a thin plastic catheter (we use Tx360 device). The SPG block can be also effective for the treatment of an acute cluster headache.

Dexamethasone (Decadron) is a strong corticosteroid (steroid) anti-inflammatory medication similar to prednisone and methylprednisolone (Medrol). Considering that inflammation occurs during a migraine attack and that non-steroidal anti-inflammatory drugs (NSAIDs) work well for migraines, you’d expect that a steroid medication would also be effective. And they do help, but mostly in combination with migraine drugs such as sumatriptan (Imitrex), rizatriptan (Maxalt) and other. In a blinded study, 4 mg of dexamethasone given along with 10 mg of rizatriptan was more effective than rizatriptan alone and it reduced the rate of migraine recurrence. Dexamethasone given intravenously in an emergency room setting also reduced the rate of migraine recurrence.

The usual oral and intravenous dose of dexamethasone is between 4 mg and 12 mg. Potential side effects include anxiety, or feeling “hyper”, depression, insomnia, dizziness, upset stomach, increased blood sugar, and other. The multitude of potential side effects is why we first try triptans (tablets and injections), NSAIDs, and nausea medications, before adding steroids. When these drugs not help and intravenous treatment is called for (and the patient is able to come to our office), before giving steroids we try magnesium sulfate, ketorolac (Toradol), ondansetron (Zofran) or metoclopramide (Reglan), and dihydroergotamine (DHE-45). We may also give nerve blocks or a sphenopalatine ganglion block to avoid giving a steroid medication.

Codeine is a mild opioid (narcotic) pain killer, which has less of an addiction potential of butorphanol, described in the previous post, or most other opioid drugs. However, it definitely can cause addiction and can be a “gateway drug” leading to the abuse of stronger prescription and illicit drugs. Some countries allow codeine to be sold without a doctor’s prescription, but it is always in a combination with other drugs. In Canada, codeine has to be mixed with two other drugs, usually with acetaminophen and caffeine and it is sold without a prescription, but from behind the counter rather than from open shelves.

A combination of codeine with caffeine, butalbital and either acetaminophen or aspirin (Fioricet with codeine and Fiorinal with codeine) is particularly problematic because caffeine can also cause medication overuse headache and butalbital is also addictive.

The main problem with codeine is that just like other opioid drugs it is not very effective and can cause or worsen nausea. If taken regularly (more than once a week) opioids can also cause medication overuse (or rebound) headache even in the absence of addiction. Codeine with acetaminophen is worth considering if triptans (sumatriptan or Imitrex and similar drugs) and NSAIDs (Advil or ibuprofen, Aleve or naproxen, and other) are ineffective or contraindicated.

I do have patients taking Fioricet or Fiorinal with codeine or codeine with acetaminophen with good relief and few side effects, but I can count those patients on the fingers of one hand.