Frequent attacks of migraine are best treated with preventive measures. Several categories of medications have been shown to be effective for the prevention of migraine headaches. These include Botox injections (for chronic migraine), epilepsy drugs (gabapentin, topiramate, divalproex), blood pressure medications (propranolol, atenolol, lisinopril, losartan, and other), as well antidepressants.

Antidepressants, like most other preventive drugs, were discovered to be effective for pain and headaches by accident. We have good scientific proof that you do not need to be depressed to obtain pain and headache relief from these drugs. The effect on pain and on anxiety or depression are independent of each other. However, many patients who have pain and headaches have higher rates of depression and anxiety and these drugs can relieve both conditions.

The oldest category of antidepressants are tricyclic antidepressants. Elavil or amitriptyline was introduced in the US in 1961. Amitriptyline has been extensively tested for a variety of painful conditions, including low back pain, neuropathy pain, migraines, and other. The main side effects of amitriptyline are dry mouth, drowsiness, constipation, and sometimes, weight gain. Other drugs in the family of tricyclic antidepressants often have fewer side effects. Many doctors always begin with nortriptyline or Pamelor, which is a derivative of amitriptyline and may have fewer side effects. Amitriptyline is broken down in the body into nortriptyline, which is less sedating. We also prescribe other tricyclics, desipramine (Norpramine), doxepin (Sinequan), and protriptyline (Vivactil), which also tend to have fewer side effects. When a patient has insomnia and is not prone to gaining wait, amitriptyline may be the better choice since it will also improve sleep.

The starting dose of amitriptyline, nortriptyline, doxepin, and desipramine is 10 or 25 mg taken at night. Then, if this starting dose is ineffective, the dose is gradually increased to 50 mg, then 75, and sometimes higher. Besides being very effective, tricyclics have another advantage – there is a blood test to measure how much of the medicine is absorbed and is circulating in the body. When a patient takes more than 75 – 100 mg without obtaining relief, we do a blood test to see if the blood level is low and we need to increase the dose or if the level is high and the drug is just ineffective. With protriptyline, the least sedating drug, the starting dose is 10 mg and the highest dose is around 30 mg. Treatment of pain and migraines usually requires a much lower dose of a tricyclic than for depression. All of the tricyclics are available in a generic form and are inexpensive.

Another category of antidepressants that relieve pain and headaches is serotonin and norepinephrine reuptake inhibitors, or SNRIs. Some of the SNRIs are FDA-approved for various painful conditions, such as neuropathy, shingles, fibromyalgia, and back pains. Most popular SNRIs are Effexor (venlafaxine), which is available in a generic form, Cymbalta (duloxetine), Pristiq (desvenlafaxine), Savella (milnacipran), and Fetzima (levomilnacipran). These drugs have fewer side effects than tricyclics, although they are sometimes difficult to stop because they can cause heightened anxiety and other withdrawal symptoms.

Nardil (phenelzine) is an antidepressant in the family of MAO inhibitors and it has also been used for the preventive treatment of migraine headaches. However, this drug has many potential serious drug-drug and drug–food interactions and most doctors avoid this medicine. Other MAOI drugs are Parnate (tranylcypromine), Emsam patch (selegiline) and other.

SSRIs are the most popular drugs for the treatment of anxiety and depression, but they are ineffective for the treatment of pain, migraines, and other headaches. These drugs include Prozac (fluoxetine), Paxil (paroxetine), Lexapro (escitalopram), Zoloft (sertraline) and other. They are very popular because they have fewer side effects than other antidepressants, although they probably cause higher rates of sexual dysfunction.

Expiration date on medications does not indicate that the medication is no longer effective or safe after that date. Having had extensive experience with the production and testing of Migralex, I can reassure you that medications remain safe and effective for years after the expiration date. An article just published in the Wall Street Journal’s “Burning Question” column addresses this issue.

The FDA has conducted a study for the Department of Defense testing 122 different drugs. The conclusion of the study was that 88% of the drugs remain effective for an average of 5 and 1/2 years after the expiration date. The main problem with expired drugs is not that they become dangerous to use, but that their efficacy slowly declines. A doctor quoted in the WSJ article says that there have been no reported cases of toxicity from expired medications. But a decline in efficacy could be a problem with life-saving drugs, such as nitroglycerin for heart, EpiPen for allergies, or insulin for diabetes.

It is very important to store the medications in a dry cool place, rather than in a medicine cabinet in the bathroom, which periodically gets hot and humid. Also, do not leave drugs in a car during the summer – the temperature in a locked car left in the sun can rise to 130 degrees and higher.

I usually advise not to use drugs beyond two years of the expiration date even if they were kept in a dry and cool place. Before using an expired drug inspect the tablet to make sure it hasn’t turned colors, smells bad, or became brittle and crumbling. Obviously, if it is an inexpensive generic drug, get a fresh bottle. However, with expensive drugs, such as some triptans (Relpax, Frova, Axert) and injections of Imitrex (sumatriptan) considerable amounts of money can be safely saved. A common scenario is a patient with cluster headaches who has a bout every couple of years and has only expired injections of Imitrex. It usually takes at least a few days to be seen by a doctor and to get a new prescription, while the attacks of cluster headaches can be devastatingly severe. Again, the worst that can happen is that the injection will be less effective, but usually it will still provide some relief.

There is a difference in how long expired drugs remain effective depending on the formulation. For example, tablets are the most stable, while creams and liquid drugs, such as drops, are least likely to last past the expiration date.

Acetaminophen is what most obstetricians recommend pregnant women take for their headaches. However, it is not very effective for migraine headaches and it is not as safe as we thought (see my recent post). Fioricet is another drug favored by some obstetrician and it is also not very effective and not very safe.

Sumatriptan (Imitrex) was introduced 20 years ago and the manufacturer has maintained a registry of women who took the drug while pregnant. The final results of this registry were just published in the journal Headache. The registry included 626 women who were exposed to sumatriptan during their pregnancies. They also followed women who took two other migraine drugs, naratriptan (Amerge) and a combination of sumatriptan with naproxen (Treximet). However, there were too few women in those groups to make any conclusions about the drugs’ safety.

As far as sumatriptan, the risk of major birth defects was not increased. The authors also reviewed several other large studies which assessed the risk of taking migraine medications during pregnancy. One of the studies were from the Swedish Medical Birth Register, which included 2257 births following first trimester sumatriptan exposure. No risk was found in this study either.

In summary, pregnant women suffering from severe migraines should be prescribed sumatriptan. Most women respond to an oral form (tablet), but those with very severe attacks should be offered an injection.

One of my patients I saw last week developed osteoporosis while taking Topamax (topiramate). Topiramate is known to cause osteoporosis by causing loss of calcium through the kidneys. While osteoporosis is not common, we don’t know if it is really that rare. A side effect that was thought to be rare (less than 1%, according to the manufacturer) when the drug was launched, is kidney stones. Now we know that close to 20% of people taking topiramate for a long time, develop kidney stones. Both kidney stones and osteoporosis occur through similar mechanisms, so it is possible that osteoporosis is also much more common than doctors think.

This patient had no other side effects and topiramate was very effective in controlling her migraines. Since osteoporosis is a very serious and potentially dangerous condition, she will have to stop taking topiramate. However, she does have other options because she has never tried Botox injections and several other drugs for the prevention of migraines.

Another very serious side effect that is not obvious to women taking Topamax, is the potential for serious problems in the fetus. The FDA designates topiramate as belonging to category D: “Pregnancy Category D drugs are those with positive evidence of human fetal risk based on human data, but still may be used in pregnant women in certain situations when its benefits are thought to outweigh potential risks”. Drugs in category B are considered to be safe in pregnancy, while category C means that there is not enough data and category X means it is absolutely contraindicated in pregnancy.

Topamax (topiramate) is one of the more popular drugs for the prevention of migraines (as well as treatment of epilepsy). It works only in half of the patients, while for the other half it doesn’t work or causes unacceptable side effects. The reason for its popularity is that unlike many other medications which can cause weight gain, this one often causes weight loss.

In addition to the side effects that occur over time, there are many that happen quickly and which are usually, but not always, patients easily linked to the drug: 1) cognitive impairment, such as inability to recall a word, slow thinking, or as some patients tell me, feeling stupid, 2) drowsiness, 3) dizziness, 4) fatigue, 5) blurred vision due to an acute glaucoma, and other.

Generic drugs provide significant savings and 80% of all prescriptions in the US are filled with generic drugs. Many doctors are skeptical when patients complain that the generic is not as good as the brand. But not all generics are created equal, literally. For example, there are about 10 generic manufacturers of Imitrex (sumatriptan). I’ve had patients tell me that certain generics, particularly the ones made by an Indian company Ranbaxy, are much less effective than the brand or generics made by other manufacturers. This problem is widespread and one of my previous posts described a study of the use of generic Topamax (topiramate) in epilepsy patients (this drug is also approved for the prevention of migraines). Patients on a generic were admitted to the hospital more often, had longer hospital stays, and were three times more likely to sustain head injury or a bone fracture.

Yesterday, The New York Times published an expose on the generic manufacturers in India. Ranbaxy was one of the generic drug makers that was reported to have the most problems. Its plants are being repeatedly shut down by the American FDA, who also imposed a $500 million fine. The article cites understaffed regulatory bodies and corruption as the main reasons for poor quality controls. One survey showed that 12% of medications sold in India contained no active ingredients, including life-saving drugs such as antibiotics and cancer drugs. It is not clear what percentage of drugs entering the US is adulterated. At least in India the FDA is allowed to inspect plants and impose fines. In China, the government has refused to let the FDA expand its monitoring. The article has this ominous ending:
“The United States has become so dependent on Chinese imports, however, that the F.D.A. may not be able to do much about the Chinese refusal. The crucial ingredients for nearly all antibiotics, steroids and many other lifesaving drugs are now made exclusively in China.”

So what can you do to protect yourself? By law, the name of the manufacturer must be printed on the medicine bottle you get from the pharmacy. If you find a generic that works well, try to stick to it. If your pharmacy suddenly changes the generic manufacturer and the drug is not as effective or causes side effects, you may want to ask them to get you the generic that worked. The big chains such as Walgreens and CVS may not be able to do it, but most independent pharmacies have more flexibility. You can also try switching from one chain to another since they often stock generics from different companies.

One more tip is from my recent previous post – check GoodRx.com for the lowest prices in your area. Also, it is not unusual for your insurance copay to be higher than the actual cost of medicine. For example, you copay could be $15 or more, while if you buy the same generic drug without insurance, it will cost you $4 or $10. And do not expect the pharmacist to tell you this.

“Daily triptan use for intractable migraine” is the title of a report by Dr. Egilius Spierings published in the latest issue of the journal Headache. This is a controversial topic, which I addressed in a previous post. Dr. Spierings, who is affiliated with both Tufts Medical Center and Harvard Medical School presents a case of a 50-year-old woman who failed trials of multiple preventive medications. This woman responded well to sumatriptan, 100 mg, which she took daily and occasionally twice a day with excellent relief and no side effects. Dr. Spierings discusses the evidence for Medication Overuse Headaches (MOH), which is common with caffeine-containing drugs, butalbital (a barbiturate), and opioid drugs (narcotics). It is less clear whether triptans cause MOH and he mentions that most patients who end up taking a daily triptan do so only after they failed many preventive (prophylactic) drugs and after they discover that they can have a normal life if they take a triptan daily. This applies not only to sumatriptan, but any other similar drug, such as Amerge (naratriptan), Zomig (zolmitriptan), Maxalt (rizatriptan), Relpax (eletriptan), and other. After 20 years of being on the market, we have no evidence that these drugs have any long-term side effects. In Europe several of these drugs are sold without a prescription. The major obstacle to their daily use has been the cost. However, several of these medications are now available in a generic form and a 100 mg sumatriptan tablet costs as little as $1.50.

Placebo effect is a curse for medical researchers. Every new treatment has to be shown to be better than placebo and placebo is often very effective. In clinical practice, unlike in research, placebo effect is a good thing, but many doctors fail to maximize its effect. If the doctor emphasizes all of the potential side effects and does not stress positive attributes of a drug, the patient is not likely to respond well. However, if the doctor is enthusiastic about the efficacy of a drug, the results can be dramatically different. Obviously, side effects need to be mentioned as well, but if the drug is really dangerous, it should not be prescribed in the first place.

The importance of placebo effect specifically with migraine drugs was described in a study published in Science Translational Medicine. The findings confirm that patients who receive positive messages about the potential efficacy of their treatment may have better treatment outcomes than patients who receive negative messages.

The study involved 66 migraine sufferers with intermittent attacks. Patients first recorded their baseline pain intensity on a scale from zero (no pain) to ten (maximal pain) for an untreated migraine attack. Then each study participant received a series of six envelopes containing treatment for six subsequent migraine attacks: two of the envelopes were labeled as “placebo”, two as “Maxalt” (rizatriptan, one of the the anti-migraine drugs called triptans) and two as “placebo or Maxalt.” However, for each pair of envelopes with identical labels, one envelope actually contained a placebo pill and the other contained Maxalt.

Patients who had taken Maxalt mislabeled as “placebo” reported roughly 50% less pain relief than those who had taken the Maxalt labeled as “Maxalt.” This suggests that more than half of the drug effect was due to the placebo effect.

The study was conducted by Rami Bursteine, Ted Kaptchuk, and other doctors at Harvard Medical School. Dr. Burstein said that labeling Maxalt as “placebo” likely reduced the effectiveness of Maxalt by giving patients negative expectations about the efficacy of the treatment. Similarly, he says, providing patients with a long list of possible side effects, risks, and adverse events in the context of prescribing a drug in clinical practice could give patients negative expectations, and therefore could potentially reduce drug efficacy, resulting in patients taking more drug.

Strikingly, the study also revealed that placebo treatment mislabeled as Maxalt was just as effective in reducing pain as Maxalt mislabeled as placebo. “No one’s ever seen that before in human history, in my knowledge,” Kaptchuk says, referring to the comparison. “It raises the possibility that the placebo effect can be harnessed directly.”

The improvement in symptoms that occurred in patients who knowingly took the placebo pill may have occurred because people often become conditioned to associate taking a pill with feeling better, although no one can explain why or how the placebo treatment works.

It is considered unethical for doctors to prescribe placebo, but they may want to consider first trying drugs that may not be the most effective, but are significantly safer than the stronger ones. One such example in my own practice pertains to the use of epilepsy drugs. Depakote (divalproex) and Topamax (topiramate) are approved by the FDA for the prevention of migraines, while Neurontin (gabapentin) is not. In fact, Neurontin is less effective, but it has significantly fewer side effects. Also, Neurontin is not dangerous if the patient were to get pregnant, while the other two drugs are.