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.

Branded triptan medications are extremely expensive with one pill of Relpax or Frova costing $30 – $40. Fortunately, Imitrex, Maxalt, Amerge, and Zomig tablets are available in a generic form. However, even the generic version of Amerge is $3 to $4 a pill, although generic Imitrex and Maxalt can be found for $2. Unfortunately, some patients respond only to Relpax, Frova or Zomig nasal spray, which insurance companies tend not to pay for. Other people need medications that are not available in the US, such as domperidone, an excellent drug for nausea or flunarizine, a calcium channel blocker for the preventive treatment of migraine (not such an excellent drug because of its side effects).

Some patients who need a branded product or one not available in the US buy drugs from online Canadian pharmacies. But how do you know if the pharmacy is legitimate? Some sites that claim being a Canadian pharmacy in fact are not Canadian and the drugs they sell are fakes. One way to find a legitimate Canadian pharmacy is to check if it is certified by the Canadian International Pharmacy Association. You can also check if the pharmacy is certified by the PharmacyChecker.com and is listed on their free website.

When buying locally, you can find a pharmacy with the cheapest price for a specific drug by going to GoodRx.com. But do not assume that if a pharmacy offers the lowest price on one drug, its prices on other drugs will also be the lowest.

Art credit: JulieMauskop.com

The approval of the lower dose Sumavel device is a good opportunity to again remind migraine sufferers about the benefits of injectable sumatriptan. Many doctors do not even mention to their patients that sumatriptan is available in an injection that is easy to self-administer. Obviously, if a tablet of sumatriptan (Imitrex) or another triptan works quickly and prevents the headache from becoming disabling, there is no need for an injection. However, when the tablet does not work fast or well enough or if nausea makes it difficult to swallow tablets, injection can be a life saver. Injections of sumatriptan are available in a variety of devices. One of them is Sumavel, an injection without a needle. This device propels the medicine through the skin as a very thin jet of fluid. It is perfect for those with needle phobia. It also has the advantage of not having to worry about the proper disposal of needles. Having a choice of a 4 mg or a 6 mg dose allows patients with frequent cluster headaches to take 3 4 mg doses in 24 hours (maximum recommended dose is 12 mg). The 4 mg dose is also useful for people who get side effects from 6 mg, since 4 mg may be sufficiently effective without causing side effects.

Topamax (topiramate) has been reported to cause inability to sweat which can lead to hyperthermia or overheating. At first, this condition was reported as a rare complication, but a study of 173 children showed that 22 of them or more than 10% developed this side effect. The ability to sweat returns when the drug is stopped. Sweating allows the body to coll off and loss of this mechanism can be dangerous in hot weather or during vigorous exercise. Those who take Topamax should speak to their doctor if they notice reduced sweating.

Topiramate is an effective drug which the FDA approved for the prevention of migraine headaches as well as epilepsy and mood disorders. However, in large clinical trials only half of the patients put on this drug for the treatment of migraines stayed on it. The other half either did not obtain relief of their migraines or developed side effects. One of the most common side effects is impairment of cognitive functions – people can’t remember names, can’t come up with the right words, or as some have told me they feel stupid. Other people become very tired from Topamax because they develop metabolic acidosis – their bodies become too acidic. Long-term side effect of kidney stones was also thought to be rare when the drug was introduced, but subsequent studies showed that up to 20% of patients develop kidney stones.

The full extent of side effects of any new drug does not become apparent until years after its introduction. This does not mean that we can afford to wait for years before trying new drugs since some of the patients who come to our center with migraine headaches do not respond to the available treatments. What we can do is monitor these patients very closely and stop the drug as soon as possible.

At the New York Headache Center we always try to avoid using medications and use alternative (i.e. non-drug) therapies first. We often succeed, but unfortunately, many of our patients do end up taking some drugs. However, when choosing among many medications, we start with the ones that are least likely to harm. Depakote (sodium valproate) is an effective drug for the treatment of epilepsy, mood disorders, and migraines. While we do prescribe Depakote to our patients, it has never been our first, second, or third choice because we already know that it can cause liver problems and fetal malformations. A recent study published in Neurology adds another reason to avoid this medication.

Patients with intractable epilepsy who were taking Depakote were compared with those who were taking other epilepsy medications and with healthy controls. MRI scans showed that those taking Depakote had thinning of the parietal lobes of the brain, had lower total brain volume, and lower white matter volume. This was a small study, but it was conducted because of previous reports of brain atrophy. Fortunately, those previous reports showed that brain atrophy was reversible when the medication was stopped. If you are taking sodium valproate for migraine headaches or a mood disorder, do not stop taking it without consulting your doctor since stopping it suddenly can worsen your condition and in epilepsy patients, cause seizures. But do discuss alternative options with your doctor, although some people may not be able to stop it if no other drugs provides relief of their symptoms.

Acute treatment of episodic and chronic migraine headaches in the US leaves a lot to be desired. Results of the American Migraine Prevalence and Prevention Study lead by Dr. Richard Lipton indicates that the acute treatment of migraine headaches in patients with chronic migraines is significantly worse than in patients with episodic migraines. Chronic migraines are defined as those occurring on 15 or more days each month, while patients who have 14 or fewer migraines a month are classified as having episodic migraines.

The researchers developed a specific questionnaire to assess acute treatment of migraine headaches. The questionnaire evaluated the effect of treatment on people’s functioning, how rapid was the relief, relief consistency, recurrence risk, and tolerability or side effects. They examined responses from 8612 persons who met criteria for migraine (chronic migraine = 539; episodic migraine = 8073). The treatment scores were significantly lower for persons with chronic migraine vs episodic migraine. The conclusion was that the questionnaire was a robust tool for measuring treatment optimization and that acute treatment was suboptimal for both episodic and chronic migraines, particularly for chronic migraines, suggesting that there are opportunities for improving care.

Art Credit: JulieMauskop.com