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Headache medications

Riboflavin (vitamin B2) has been a popular supplement for the prevention of migraine headaches. The evidence for its efficacy is limited. Only one small double-blind, placebo-controlled trial showed that a very high dose of riboflavin (400 mg daily) is better than a placebo. The study included only 55 patients, which makes the results not very reliable. Besides, the difference between the riboflavin and the placebo groups appeared only in the third month. There was no difference during the first two months. This study was published over 20 years ago and my clinical impression over this long period of time has been fairly negative.

A study just published in the journal Headache examined dietary intake of riboflavin and thiamine (vitamin B1) and correlated it with the occurrence of migraines or severe headaches. The researchers used the data from 13,439 adult participants in the National Health and Nutrition Examination Survey conducted between 1999 and 2004 in the United States. They found that people with a high intake of thiamine were significantly less likely to suffer from severe headaches or migraines. This was more pronounced in women. They found no such association for riboflavin.

Supplements with the most evidence in treating migraines are magnesium and CoQ10. I recommend riboflavin, folate (vitamin B9) and vitamin B12, to patients with an elevated homocysteine level. Excessive amounts of this amino acid are damaging to blood vessels and may be responsible for the increased risk of strokes in patients who have migraine with aura. It is worth checking homocysteine levels in all patients who have migraine auras, even if the auras occur infrequently.

“B complex” is a popular combination of various B vitamins. This latest paper is making me consider adding B complex rather than individual B vitamins to magnesium and CoQ10 in all of my migraine patients.

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Psychedelics are being actively studied for depression and post-traumatic stress disorder (PTSD). These trials usually involve hallucinogenic doses. Microdosing psychedelic substances such as psilocybin, lysergic acid diethylamide (LSD), and methylenedioxymethamphetamine (MDMA) has become a popular treatment for depression. Microdosing means that the amount of a psychedelic is too low to cause hallucinations or other overt sensory experiences.

There is an accumulation of evidence that psychedelics can provide pain relief. A case series just published in the journal Pain describes three patients with chronic pain who obtained significant relief from microdosing psilocybin-containing mushrooms.

The first patient was a 37-year-old man with severe pain due to traumatic quadriplegia. He had almost complete relief of pain and was able to stop taking tramadol, an opioid analgesic, diazepam (Valium), and marijuana. The relief was ongoing for six months when he was last seen by the doctors.

The second patient was a 69-year-old woman with complex regional pain syndrome (also known as reflex sympathetic dystrophy) secondary to left leg trauma. She had tried nerve blocks, other invasive procedures, stem cell injections, acupuncture, opioid analgesics, and many other medications, all with no relief. At the time of the published report, microdosing was providing continued significant relief for over a year.

The third patient was a 40-year-old woman with pain in her leg due to degenerative disk disease in her spine. Her pain did not improve with epidural injections, back surgery, muscle relaxants, opioid drugs, and physical therapy. Psychedelic mushrooms had a profound effect on her pain.

Psychedelic mushrooms have been reported by many patients to be effective in the treatment of cluster headaches (see ClusterBusters.org). A small double-blind study by Yale researchers showed a beneficial effect of synthetic psilocybin in treating migraine headaches.

It remains to be proven that sub-hallucinogenic doses of psychedelic drugs provide relief of painful conditions. If proven effective, however, such drugs will offer a much safer option than any opioid and NSAID analgesics, epilepsy drugs, antidepressants, or any other prescription drug. They are very safe even at hallucinogenic doses.

I am often asked about the practical side of using psychedelic mushrooms – where to buy them, how much to take, and for how long. Since the state of NY, unlike some other states, has not legalized or decriminalized the use of psychedelic mushrooms, I cannot answer these questions. Even if it was legal for me to do, I would not have reliable answers until clinical trials give us good data.

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It was an honor to speak in Israel at the 6th Annual International Headache Symposium along with past presidents of the International Headache Society, Drs. Messoud Ashina and Alan Rapaport, the current IHS president, Cristina Tassorelli, the president-elect, Dr. Rami Burstein, and other leading headache experts. The symposium was organized by the President of the Israeli Headache Association, Dr. Oved Daniel, and by Dr. Arieh Kuritzky.

 

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No, Daxxify is not really a competitor in the treatment of chronic migraines or any other medical condition. Daxxify, a new botulinum toxin, was just approved by the FDA only for cosmetic use. Daxxify does stand out from five other botulinum toxin brands in that its effect lasts longer. The other toxins are Xeomin, Dysport, Jeuveau, and Myobloc. Myobloc is approved only for medical conditions, Jeuveau only for cosmetics, and Xeomin and Dysport are approved for both cosmetics and a few medical conditions.

Initially, Botox was approved by the FDA in 1989 to treat eye problems. Since then, it has been approved for many medical and cosmetic indications, including chronic migraine. None of the other toxins are approved for such a wide range of indications. It remains by far the most widely used type of botulinum toxin with tens of millions of people treated for medical and cosmetic reasons.

Yes, having a longer-acting botulinum toxin is an advantage. You will need to have less frequent treatments. However, if you have any side effects, they will also take longer to go away. We are talking mostly about cosmetic side effects, such as droopy eyelids. When treating headaches, with proper technique, side effects are uncommon. These may include weakness of the neck muscles or, if treating TMJ syndrome, difficulty chewing.

Since Botox is approved by the FDA for chronic migraines, Botox is the drug insurance companies cover. Allergan (a division of Abbvie), the manufacturer of Botox, has many more years left on their patent to treat chronic migraines. Botulinum toxin is a biological product (made by bacteria rather than synthesized from chemicals) and every version of it is slightly different. This is why when Allergan’s patent to treat migraines expires, the competitors will have to conduct large trials to prove that their product is also effective for migraines.

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Patients with chronic migraine who were started on Botox were significantly more likely to continue to be treated with Botox after one year than patients who were started on a CGRP monoclonal antibody (mAb). mAbs are given monthly by injection. This category includes erenumab (Aimovig), fremanezumab (Ajovy), and galcanezumab (Emgality).

The results of this large retrospective study that included 1,974 patients were presented at the last meeting of the American Headache Society held in June of this year. The lead authors were Dr. Todd Schwedt of the Mayo Clinic and Dr. Andrew Blumenfeld.

The study was sponsored by the manufacturer of Botox which makes it inherently biased. However, the difference between the two groups was striking. Of patients who were started on Botox, 66% continued the treatment at the end of the year. Less than a third of patients who were started on a mAb were still getting it at the end of the year.

The researchers looked at differences in outcomes in patients enrolled before and during COVID. The results were similar before and during the pandemic. This is surprising because, during the pandemic, many patients were reluctant to come to the office for Botox injections. Many preferred to self-inject mAbs at home. Despite this obstacle, Botox patients were twice as likely to continue treatment at the end of the year.

Besides efficacy, the major reason I recommend Botox ahead of mAbs and other drugs is its proven long-term safety. Botox was first approved by the FDA in 1989. Botox is my preferred treatment for chronic migraines even in pregnant women.

Both mAbs and Botox are fairly expensive. The same group of researchers presented a second study that evaluated all-cause and migraine-related costs in these two groups of patients. They found no difference in total healthcare costs and migraine-related costs, including emergency department expenses.

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Two out of three women stop having migraines during pregnancy, especially in the second and third trimester. The difficult question is how to treat migraines in the first trimester and in women whose migraines do not improve or get worse in pregnancy.

Acetaminophen (Tylenol, paracetamol) is considered safe in pregnancy and that is what many women take for migraines and other pains. Unfortunately, acetaminophen is usually ineffective for severe migraines. It is also not as safe as many physicians and the general public thinks. Several studies indicate that acetaminophen increases the risk of attention-deficit hyperactivity disorder (ADHD) and with heavy use, possibly even autism spectrum disorder.

Some obstetricians strongly advise against taking any migraine medications. However, the stress of an acute migraine attack with severe pain, vomiting, and dehydration is likely to have a deleterious effect on the fetus. A Danish study of 22,841 pregnancies among women with migraine showed that untreated migraine leads to an increased risk of low birth weight, preterm birth, and cesarean delivery.

A report just published in the journal of the American Medical Association (JAMA) examined “Association of Maternal Use of Triptans During Pregnancy With Risk of Attention-Deficit/Hyperactivity Disorder in Offspring”.

The study used the data from the Norwegian Mother, Father and Child Cohort Study, linked to the Medical Birth Registry of Norway, the Norwegian Patient Registry, and the Norwegian Prescription Database using the mother’s personal identification number. The conclusion of this large and rigorous study was: “This cohort study found no association between prenatal triptan exposure and ADHD diagnosis or ADHD symptoms at 5 years of age. This study adds to the growing literature on the safety of triptan use during pregnancy and expands it to an important neurobehavioral outcome.”

Triptans have been available without a prescription in all European countries for over a decade. In the US, triptans are available only by prescription. This is one of the reasons for the perception of acetaminophen as being more benign than sumatriptan and other triptans. The opposite is likely to be true. If you are a pregnant woman suffering from severe migraines, ask your doctor for a prescription for sumatriptan.

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A paper presented at the annual meeting of the American Headache Society that is taking place this weekend examined the risk of major adverse cardiovascular events (MACE) in patients with preexisting cardiovascular (CV) conditions. The researchers compared the risk of triptans with that of opioid/barbiturate drugs (drugs like codeine, Vicodin, Percocet, Fioricet) and non-steroidal anti-inflammatory drugs (NSAIDs).

They used Mass General Brigham Research Patient Data Registry database to identify 12,121 prescriptions. Of these, 33% were for triptans, 50% for opioid/barbiturate drugs, and 17% for NSAIDs.

MACE occurred in 1% of those taking triptans, 4.5% taking opioid/barbiturate drugs, and 3.8% taking NSAIDs.

This goes against the established dogma of avoiding triptans in patients with CV problems. Instead, doctors are advised to offer opioid/barbiturate drugs or NSAIDs. Unfortunately, according to the FDA-approved package insert, triptans are contraindicated in patients with CV, cerebrovascular, and peripheral vascular problems. This contraindication came about from purely theoretical reasoning rather than real-life experience. Triptans do in fact have mild vasoconstriction properties and it is possible that someone with severe occlusion of coronary or other blood vessels can have dangerous constriction of a blood vessel. There have been also reports of healthy people developing cardiovascular complications, but those are very rare.

This new data indicates that triptans are safer than the alternatives most doctors prescribe. The two alternatives described in the report also carry significant risks of addiction, stomach ulcers, and bleeding. It is very likely, however, that doctors will continue to avoid prescribing triptans in this population because of legal concerns and ingrained habits.

We do have two new classes of drugs to treat an acute migraine attack that are proven to be safe in patients with CV conditions. These are gepants – rimegepant (Nurtec) and ubrogepant (Ubrelvy) as well as ditans – lasmiditan (Reyvow). These drugs are very expensive and insurers always require that patients first try other drugs.

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Sumatriptan (Imitrex) and other triptans have been available without a prescription in all European countries for over a decade. A new study by Austrian researchers published in the current issue of Headache confirms the outstanding safety of these drugs.

The study looked at 13,833 people over 50 years of age who were prescribed a triptan in 2011, the year before triptans became available over-the-counter. The comparison group included 41,400 triptan non-users. Of the 13,833, 19% were older than 65. The researchers established that 16% “overused” triptans, defined as getting more than 30 doses in a 90-day period, although the concept of “overuse” clearly lacks a scientific basis.

They discovered that those who were taking triptans did not spend more time in a hospital. They also did not have a higher frequency of heart attacks, hypertension, irregular heartbeats (arrhythmias), strokes, circulation problems in their extremities, or other vascular problems. This was true even for those who “overused” triptans.

These findings are consistent with the “Consensus Statement: Cardiovascular Safety Profile of Triptans in the Acute Treatment of Migraine” by the Triptan Cardiovascular Safety Expert Panel published in 2004. It states “The incidence of serious cardiovascular events with triptans in clinical trials and clinical practice appears to be extremely low “.

Unfortunately, in the US triptans are available only by prescription. About 15 years ago, the FDA blocked an application by the American Home Products (a company that Pfizer later acquired) to launch over-the-counter sumatriptan. This greatly restricts access to a highly effective and safe migraine drug. Many physicians remain under the impression that triptans cause heart attacks, strokes, and other dangerous side effects. My patients often tell me that this is what their previous doctor warned them about.

It is clear that triptans are safer than Excedrin, aspirin, ibuprofen, or naproxen. Several dozen of my patients have been taking triptans daily for years. They do not have medication overuse headaches, do not suffer any long-term side effects, and do enjoy disability-free life.

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Not surprisingly, none of the new migraine drugs have been tested in pregnant women. No new drug for any indication is ever tested for its safety in human pregnancy. They are always tested in pregnant animals, which helps weed out most drugs that are clearly dangerous. It takes decades to learn if a drug is safe. This happens through an accumulation of anecdotal reports and pregnancy registries that are usually run by drug manufacturers.

Erenumab (Aimovig) was the first CGRP monoclonal antibody to be approved for the preventive treatment of migraines four years ago. It was tested in pregnant monkeys who were given 50 times higher doses (by weight) than the FDA-approved dose for humans. Even though some of the medicine crossed the placenta into baby monkeys, they had no developmental problems.

In the current issue of Headache, University of Texas doctors published a report of a woman who continued to inject herself with erenumab throughout the duration of her pregnancy. She tried to stop the drug before planning to get pregnant but her severe migraines recurred. Her baby was born healthy and had normal development by the last evaluation at 6 months of age.

This case report is the first very small but important step in the process of evaluating the safety of erenumab in pregnancy.

In humans, the transfer of antibodies, which are large molecules, across the placenta is very limited before the 16th week of pregnancy and increases after the 22nd week. We still recommend stopping the drug about five months before a pregnancy is planned. If a woman, however, does get pregnant, intentionally or not, the risk of complications is low if erenumab is stopped within the first three months of pregnancy. This also applies to all other monoclonal antibodies in general and specifically other migraine drugs – galcanezumab (Emgality), fremanezumab (Ajovy ), and eptinezumab (Vyepti).

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Rimegepant (Nurtec ODT) was just approved by the European Medicines Agency for marketing in 27 EU countries as well as Iceland, Liechtenstein, and Norway. It was approved for both the acute treatment of migraine with or without aura, and prophylaxis (prevention) of episodic migraine in adults who have at least four migraine attacks per month. The drug will be sold under the name VYDURA.

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If you are “overusing” acute migraine medications, preventive migraine treatments still work very well. This was the conclusion of a study that was just published in the journal of the American Academy of Neurology, Neurology.

The concept of medication overuse headache (MOH) has remained controversial. The majority of headache specialists believe in its existence. And that is what it is, a belief. There are correlational studies showing that those who take acute migraine drugs tend to have them more often as time goes on. This obviously does not mean that the drug is responsible for the increase in frequency. It is more likely that people take drugs more often because their headaches have gotten worse. There is proof for the existence of MOH only for two drugs – caffeine and opioid (narcotic) pain drugs. Triptans and NSAIDs have no such proof and in my 30 years of experience, they rarely cause MOH.

The daily use of triptans is the topic of my most popular post in the 15 years of writing this blog. It received about 400 comments. Many people commented how relieved they are that taking triptans daily can be safe and effective. They often lament that they can’t get their doctors to prescribe a sufficient quantity of pills.

I am not suggesting that taking triptans daily is the first or second option. It is always better to try Botox and non-drug approaches. Taking a triptan daily, however, is probably safer than taking FRA-approved epilepsy drugs such as topiramate (Topamax) or divalproex (Depakote), or even an antidepressant.

The article in Neurology describes a large study with over 700 participants who were “overusing” acute migraine medications. Half of them were taken off these drugs and started on preventive therapies and the other half were given preventive therapies without stopping acute drugs. Both groups did equally well. This goes against the old dogma that preventive therapies will be ineffective if the daily abortive drugs are not stopped first. The most common preventive treatments in this study were topiramate, Botox, and amitriptyline (Elavil).

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Cluster headaches are considered to cause the worst pain imaginable. We have a variety of medications – both acute and preventive – that help relieve the pain of cluster headaches. For some, none of these treatments work and we do need additional medications. Ketamine could be one such drug.

Ketamine has been in use for over 50 years. Its main indication is intravenous anesthesia. Recently, the FDA approved ketamine nasal spray for depression. It is also being widely used intravenously and by mouth for depression, chronic pain, and migraine headaches. A group of researchers at the Danish Headache Center in Glostrup, Denmark tested the efficacy of ketamine nasal spray for the acute treatment of cluster headaches.

Anja Petersen and her colleagues selected 20 cluster patients whose attacks did not respond sufficiently well to sumatriptan or oxygen – the two most effective acute therapies for cluster headaches. Patients treated a single cluster attack with 15 mg of intranasal ketamine. They could repeat this dose every 6 minutes, for up to 5 times. Four patients took another medication after 15 minutes. Of the 16 remaining ones, 11 had a drop in pain severity by an average of four points, to four or lower on a one to 10 scale. Half of the patients preferred ketamine to oxygen and/or sumatriptan injection. No patient had any serious side effects from ketamine during the trial.

Ketamine nasal spray that is approved for depression is a more potent version of ketamine called esketamine (Spravato). It is a patented and branded product and it is very expensive. Ketamine itself, however, is a cheap drug. A compounding pharmacy can prepare a nasal spray for as little as $60 for a month supply. Most insurers do not cover compounded drugs, so you’d have to pay for it.

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