Imbalance of many hormones produced by our endocrine system can lead to headaches. Here is a brief summary of the hormones linked to headaches.

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Trigeminal neuralgia (TN) is an excruciatingly painful disorder which affects about one in a thousand people. Patients describe the pain of TN as an electric shock going through the face. Eating and talking often triggers the pain, so some patients become malnourished and depressed. The pain is brief, but can be so frequent and severe that it causes severe disability, weight loss, severe anxiety, and depression. The good news is that most people can obtain relief by taking drugs, such as Tegretol (carbamazepine), Trileptal (oxcarbazepine), Dilantin (phenytoin), or Lioresal (baclofen). I have successfully treated several patients who did not respond to these medications with Botox injections.

Patients who do not respond to medications or Botox injections have several surgical options available. According to a new Dutch “Nationwide study of three invasive treatments for trigeminal neuralgia” published in journal Pain shows that every year about 1% of those suffering from TN undergo surgery. Of the three most common types of surgery, percutaneous radiofrequency thermocoagulation (PRT) is by far most popular – in a three year period in Holland, 672 patients underwent PRT, 87 underwent microvascular decompression (MVD), and 39 underwent partial sensory rhizotomy (PSR). The latter two procedures a performed by neurosurgeons (MVD requires opening of the skull), while PRT is usually done by anesthesiologists (a probe is inserted through the cheek to the nerve ganglion under X-ray guidance). MVD was most effective, but caused more complications than PRT, although fewer than with PSR. More patients having PRT had to have a repeat procedure, but it was still safer than the other two. Very often the physician under-treats during the first treatment of PRT in order to avoid complications. Overall, the best initial procedure for those suffering with TN is PRT and if repeated PRTs fail, MVD can often cure this condition.

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Tylenol (acetaminophen, or in Europe it is called paracetamol) is the go-to drug for pain, headaches, and fever during pregnancy. A new study just published in the journal JAMA Pediatrics indicates that this drug may not be as safe as previously thought.

Animal research has long suggested that acetaminophen is a so called hormone disruptor, a substance that changes the normal balance of hormones. It is a well-established fact that an abnormal hormonal exposures in pregnancy may influence fetal brain development.

Danish researchers decided to evaluate whether prenatal exposure to acetaminophen increases the risk for developing attention-deficit/hyperactivity disorder (ADHD) in children. They studied 64,322 live-born children and mothers enrolled in the Danish National Birth Cohort during 1996-2002.

The doctors used parental reports of behavioral problems in children 7 years of age using a specific questionnaire, retrieved diagnoses from the Danish National Hospital Registry or the Danish Psychiatric Central Registry, and identified ADHD prescriptions (mainly Ritalin) for children from the Danish Prescription Registry.

More than half of all mothers reported acetaminophen use while pregnant. Children whose mothers used acetaminophen during pregnancy were at about 1.3 times higher risk for receiving a hospital diagnosis of ADHD, use of ADHD medications, or having ADHD-like behaviors at age 7 years. Stronger associations were observed with use in more than 1 trimester during pregnancy and with higher frequency of intake of acetaminophen.

The researchers concluded that maternal acetaminophen use during pregnancy is associated with a higher risk for ADHD-like behaviors in children.

This presents a difficult problem in treating headaches and pain in pregnant women. Aspirin and other non-steroidal anti-inflammatory drugs such as ibuprofen and naproxen can cause other problems in pregnancy and are particularly dangerous in the third trimester. In women with migraines, acetaminophen tends to be ineffective anyway, so these women should be given migraine-specific drugs, such as triptans (Imitrex or sumatriptan, Maxalt or rizatriptan, and other). They are much more effective than acetaminophen and the woman may need to take much less of these drugs than of acetaminophen. Triptans are also in category C in pregnancy, which means that we do not know how safe they are. Imitrex was introduced more than 20 years ago and we do not that it does not have any major risks for the fetus, but that does not mean that more subtle problems, such as ADHD are also not more common. Another headache drug that should be avoided in pregnancy is Fioricet. It is popular with some obstetricians because it has been on the market for 40 years. However, it contains not only acetaminophen, but also caffeine, which can make headaches worse, as well as a barbiturate drug butalbital, which can also have deleterious effect on the fetal brain.

Fortunately, two out of three women stop having migraines during pregnancy, especially in the second and third trimester. If they continue having headaches, treatment is directed at prevention. Regular aerobic exercise, getting enough sleep, regular meals, good hydration, avoiding caffeine, learning biofeedback, meditation or another form of relaxation, magnesium supplementation, are all safe and can be very effective. Acute treatments that do not involve drugs are often not very practical for a busy person. However, if the headache prevents normal functioning anyway, taking a hot bath with an ice pack on the head at the same time can help some women. Taking a nap, getting a massage, aromatherapy with peppermint and lavender essential oils are good options. For nausea, ginger and Sea Bands are sometimes very effective.

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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.

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Vitamin D has been reported to be low in patients with migraines as well as a host of other medical conditions. The big question is whether this is just a coincidence or a cause-and-effect relationship. In some conditions, such as multiple sclerosis, people with higher vitamin D levels have fewer relapses than those with lower levels, indicating a direct benefit of vitamin D. In other diseases, such as Alzheimer’s, strokes, and migraine this relationship is not clear.

A new study by Iranian doctors published in BioMed Research International shows that vitamin D deficiency is found in about half of 105 migraine patients they tested. However, when they looked at 110 matched controls without migraines, they found that half of them were also deficient. They also found that those with more severe migraines did not have lower levels than those with milder ones. This strongly suggests that vitamin D has no effect on migraine headaches.

So if you suffer from migraines, do not expect vitamin D to improve your headaches. However, if your blood test shows a deficiency, you should definitely take a vitamin D supplement to avoid some known and possibly some yet unknown problems. Taking the daily recommended dose of 600 units may not be sufficient and you may need to recheck your level to make sure that you are absorbing it. Some of my patients have needed as much as 5,000 units daily to get their vitamin D level to normal range.

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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.

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Children with migraine headaches are usually given acetaminophen (Tylenol) or ibuprofen (Advil). A group of Italian doctors compared responses to these two drugs in kids with migraines who took a daily magnesium supplement to those who did not. Results of their study were published in the latest issue of the journal Headache. One hundred sixty children (80 boys and 80 girls) aged 5-16 years were enrolled and assigned to four groups to receive a treatment with acetaminophen or ibuprofen without or with magnesium. The dose of each drug was adjusted according to the child’s weight. Those children who were in the magnesium arm were given 400 mg of magnesium (the article does not mention which salt of magnesium was given – oxide, glycinate, citrate, or another). Migraine pain severity and monthly frequency were similar in the four groups before the start of the study. Both acetaminophen and ibuprofen produced a significant decrease in pain intensity, but not surprisingly, did not change the frequency of attacks. Magnesium intake induced a significant decrease in pain intensity in both acetaminophen- and ibuprofen-treated children and also significantly reduced the time to pain relief with acetaminophen but not ibuprofen. In both acetaminophen and ibuprofen groups, magnesium supplementation significantly reduced the attack frequency after 3 and 18 months of supplementation.

This study was not the most rigorous because it did not include a placebo group as the authors felt that placing children on a placebo would be unethical. However, it was rigorous in other respects and still provides useful information. The first conclusion is that taking magnesium reduces the frequency of migraines in children. The second is that taking magnesium significantly improves the efficacy of acetaminophen and ibuprofen.

The bottom line is that every child (and adult for that matter) should be taking a magnesium supplement. I have written extensively on the importance of magnesium because our research and that of others, including the above study, has consistently shown the benefits of magnesium. Unfortunately, after dozens of publications, hundreds of lectures, and recommendations from medical societies, many doctors still do not recommend magnesium to their migraine patients. Some are not familiar with the research, others dismiss any supplements out of hand, and yet others do not believe the studies because they think that magnesium is too simple and too cheap to be effective. Most doctors are trained to prescribe drugs and they feel that patients expect prescription drugs, so giving them a supplement will disappoint the patient and will reduce doctor’s standing in patients’ eyes. This is clearly not the case since many people prefer more natural approaches and because recommending a supplement does not mean that a prescription drug cannot be also given. In fact, magnesium improves not only the efficacy of acetaminophen and ibuprofen, but also prescription drugs such as sumatriptan (Imitrex).

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White matter lesions that often seen on MRI scans of adult migraine sufferers were also found in children. A study by Washington University researchers inn St. Louis examined MRI scans of 926 children 2 to 17 years of age (mean age was 12.4 and 60% were girls) who were diagnosed with migraine headaches. They found white matter lesions (WMLs) in about 4% or 39 of these children, which is not much higher than in kids without migraines. Just like in the adults, these WMLs were slightly more common in kids with migraine with aura. None of these lesions were big enough to be called a mini-stroke or an infarct. There was no correlation between the number of lesions and the frequency or the duration of migraines. In conclusion, WMLs in children with migraines do not appear to be caused by migraines and are most likely benign in origin. The origin, however remains unknown, which often causes anxiety in parents of these children.

Unlike in children, adults with migraines and especially those with migraines with aura, are much more likely to have WMLs than adults without migraines. But even in adults, these appear to be benign as I mentioned in my previous post.

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“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.

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Many headache sufferers take over-the-counter medications which can cause upset stomach and heartburn due to reflux. Many will then resort to taking acid lowering drugs. These drugs reduce acidity which also impairs absorption of various vitamins and minerals, including vitamin B12, D, magnesium, and other. Magnesium deficiency is known to worsen migraine and cluster headaches.

The most popular drugs for indigestion, reflux, and stomach ulcers are so called proton-pump inhibitors, or PPIs (Prilosec, Protonix, Nexium, and other), and histamine 2 receptor antagonists (Zantac, Tagamet), and they are available by prescription and over the counter. Over 150 million prescriptions were written for PPIs alone last year.

A new study, published in The Journal of the American Medical Association by Dr. D. Corley and his colleagues shows that people who are taking these medications are more likely than the average person to be vitamin B12 deficient.

The study was performed at Kaiser Permanente. It involved 25,956 adults who were found to have vitamin B12 deficiency between 1997 and 2011, and who were compared with 184,199 patients without B12 deficiency during that period.

Patients who took acid lowering drugs for more than two years were 65 percent more likely to have a vitamin B12 deficiency. Higher doses of PPIs were more strongly associated with the vitamin deficiency, as well.

Twelve percent of patients deficient in vitamin B12 had used PPIs for two years or more, compared with 7.2 percent of control patients. The risk of deficiency was less pronounced among patients using drugs like Zantac and Tagamet long term: 4.2 percent, compared with 3.2 percent of nonusers.

The new study is the largest to date to demonstrate a link between taking acid suppressants and vitamin B12 deficiency across age groups. Earlier small studies focused primarily on the elderly.

The surprise was that the association was strongest in adults younger than age 30, since in the past only elderly were suspected to be at risk.

Vitamin B12 deficiency has been very common even in people not taking PPIs. This is in part due to healthier diets, which are often low in vitamin B12 which is found in high amounts in meat and liver. Vegetarians are particularly at risk.

Vitamin B12 deficiency is a serious condition, which in severe cases can be fatal. It can present with fatigue, memory impairment, tingling, weakness, dizziness, worsening headaches, anemia, and other symptoms.

Dr. Corley and his colleagues do not recommended stopping PPIs or similar drugs in people with clear need for these drugs. However, studies have found that the drugs are often overused or used for longer than necessary. One reason for this is that stopping PPIs often causes “rebound” increase in reflux making people think that they must continue taking these drugs. The way to get off PPIs is to first switch to Zantac and antacids, such as Tums or Mylanta. After a few weeks, stop taking Zantac and continue only antacids. Avoid eating foods that worsen reflux, such as chocolate, alcohol, and other, and you may need the antacids only occasionally.

Besides vitamin B12 deficiency, prolonged use of PPIs leads to other problems, including increased risk of bone fractures, pneumonia, and a serious gastro-ointestinal infection with C. difficile.

To see whether study patients were not just low in vitmain B12 but also had symptoms of deficiency, researchers reviewed the charts of 20 randomly selected PPI-using patients to determine why they had their vitamin B12 levels tested. Twenty five percent of that small sample had also been tested for anemia and 15 percent for memory loss. This indicates that many people with this deficiency have symptoms. However, because the symptoms are vague and not specific for this deficiency, doctors often ignore them and do not order any tests.

To complicate matters, when doctors do test for vitamin B12 deficiency, the test they use is not very accurate. Many laboratories list normal levels being between 200 and 1,000. However, many patients with levels below 400, and some even with levels above 400 still have a deficiency. If a deficiency is strongly suspected, additional tests are needed – homocysteine and methylmalonic acid levels.


Art credit: JulieMauskop.com

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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.

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Strenuous mental activity seems to delay recovery after a head injury, according to a new study published in Pediatrics .

Doctors have always recommended rest after a head injury, but it has never been clear how much to limit activities, what kind to limit (physical, mental, or both), and for how long.

Dr. William P. Meehan III, director of the Micheli Center for Sports Injury Prevention in Waltham, Massachusetts and his colleagues studied 335 patients (62% were males), aged 8 to 23 who came to a sports concussion clinic within three weeks of their injury between 2009 and 2011. Most of the concussions were sustained while playing ice hockey, football, basketball or soccer. The researchers asked them about their symptoms and how often they were reading, doing homework or playing games at each of their appointments.

Those with minimal cognitive activity were not reading or doing homework, and spent less than 20 minutes on the Internet or playing video games each day. They could have watched TV or movies or listened to music. Those with moderate or significant cognitive activity did some reading and some homework, but less than usual. Others had not limited their cognitive activities at all since their last clinic visit.

On average, patients took 43 days to fully recover from their concussions. Those with more minor concussions tended to get over their symptoms faster. So did those who did less with their brains while recovering.

Results showed that only those engaging in the highest levels of cognitive activity had a substantial increase in their symptom duration, while those at all lower activity levels seemed to recover at about the same pace.

According to Dr. Meehan, “This would suggest that while vigorous cognitive exertion is detrimental to recovery, milder levels of cognitive exertion do not seem to prolong recovery substantially”

In general, Meehan said, doctors recommend almost complete brain rest for three to five days after a concussion, followed by a gradual return to normal activities.

Athletes suspected of having a concussion should be seen by the most immediately available medical personnel, like an athletic trainer or team doctor, he said, with a follow-up visit to their primary care doctor.

I would also emphasize the importance of physical rest and complete avoidance of any activities that could result in another head injury before completely recovering from the first one. Complete recovery means no symptoms at all, including headaches, dizziness, mental fog, fatigue, difficulty concentrating, insomnia, anxiety, depression, and other. Taking a magnesium supplement can also help since animal studies show magnesium depletion following an injury. If rest alone does not lead to a complete recovery, cognitive behavioral therapy, medications (for anxiety, depression, and irritability), and Botox injections (for persistent headaches) are sometimes needed.

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