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Chronic migraine

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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With tens of millions of Americans suffering from migraines, access to care is a major problem. Cove, a telemedicine startup, offers a practical and affordable solution. They deliver evidence-based therapies to patients in need. To prove that their approach works, Cove collects and analyzes vast amounts of data. The study I just presented at the annual scientific meeting of the American Headache Society shows that with Cove underserved minorities obtain excellent outcomes that are equal to those of whites.
Disclosure: I am a paid consultant to Cove.

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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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Yesterday I saw a 48-year-old man who has been suffering from migraine headaches since his teens. He did not respond to a wide variety of drugs and non-drug therapies, but Emgality has been very effective. The only problem is that the effect lasts three and a half weeks. During the week before the next shot, his migraine headaches become severe and frequent. Sumatriptan helps but his disability as measured by the MIDAS scale is in the moderate range. He is a high-level executive in a large corporation and needs better control of his migraines. He had tried the other two monoclonal antibodies for migraines – Aimovig and Ajovy – and they were less effective.

Fortunately, there is a good solution to his problem. I advised him to take Emgality injections every three and a half weeks. This is a higher frequency than what is recommended by the FDA and some doctors and patients may have concerns about the safety. The one-month interval is based on averages derived from large studies. People, however, are not average. Some metabolize drugs faster or need a higher or a lower dose of a drug. Another reassuring fact about Emgality is that it is approved at a much higher dose for cluster headaches. For migraine, we give a 240 mg loading dose and then, 120 mg monthly. Patients with cluster headaches get monthly injections of 300 mg.

I have patients who have the same problem of the short duration of effect with Aimovig and Ajovy as well.

A major obstacle to the more frequent use of these drugs is the fact that insurance companies will only pay for 12 shots a year. These drugs cost about $600 to $700 a dose, so the cost is a major factor for many people. The way I get around it is by providing patients with free samples. Because we have three similar competing drugs, we get samples of all three. If you are having a similar problem, ask your doctor for a free sample. Some academic centers and large hospitals do not allow doctors to receive samples but most doctors in private practice can get them.

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I recently saw a 32-year-old woman who never suffered from headaches until a year ago when she was given an injection of a COVID vaccine (J&J). Her headache started the day after vaccination and it has persisted unabated. Besides severe daily headaches, she developed profound fatigue, muscle aches, and brain fog, making her unable to work. Her headaches had all the features of chronic migraines and I recommended trying Botox injections along with a migraine medication that she has not yet tried.

I’ve seen a few dozen patients who developed less devastating headaches or whose preexisting migraines worsened after vaccination. Some developed a headache after the first or second shot and a few had it only after the booster. I am not suggesting that people should avoid the COVID vaccine. I’ve had three shots myself. I am writing about this because of a study just published by European researchers in the Journal of Headache and Pain“Headache onset after vaccination against SARS-CoV-2: a systematic literature review and meta-analysis.”

They examined the results of 84 scientific reports that included 1.57 million participants, 94% of whom received Pfizer or Oxford-AstraZeneca vaccines. They discovered that vaccines were associated with a doubling of the risk of developing a headache within 7 days from the injection compared to people who received a placebo injection. They did not find a difference between the two different vaccine types. Some people developed a headache within the first 24 hours. In approximately one-third of the cases, headache had migraine-like features with pulsating quality, phonophobia, and photophobia. In 40 to 60% the headache was aggravated by physical activity, which is another migraine feature.

The majority of patients used some medication to treat their headaches. People reported that the most effective drug was aspirin, although the details about various treatments were not provided. We do know that in Europe doctors are much less likely to prescribe medications, including triptans. It is likely that early and aggressive treatment can prevent these headaches from becoming chronic and disabling.

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I am happy to announce that you can attend the Migraine World Summit free of charge. It is back on March 16-24, 2022 for its 7th annual virtual event. As one of the former presenters, I can tell you that you may greatly benefit from learning about the latest research on how to best manage migraine.

Migraine World Summit is a 9-day event where 32 of the world’s leading experts on migraine and headache research are interviewed on topics voted on by real patients. These interviews are online and can be accessed from anywhere in the world, but are only available free during the 9-day event.

Get your ticket today at MigraineWorldSummit.com

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Worsening of headaches in children is one of many deleterious effects of the pandemic and measures to control it. A survey of children in a headache clinic at the Children’s National Hospital in Washington DC by Dr. DiSabella and his colleagues showed that 46% of children had worsening of their migraine headaches during the pandemic.

They also reported much higher rates of anxiety, depression, and stress. Two-thirds of children reported that they exercised less. This could be one of the contributing factors since exercise has been shown to reduce the frequency and the severity of headaches.

What this survey did not explore is the effect of family stress and the presence of child abuse. Reports of child abuse have actually declined during the pandemic because most of these reports come from teachers. Chronic migraines and chronic pain are much more common in patients with a history of being physically, emotionally, or physically abused. PTSD from other causes has a similar predisposing effect and many children and adults have been traumatized by the pandemic.

Some children (as well as adults) report improvement of their headaches during the pandemic. My patients tell me that because they do not have to commute, they have more time to exercise, meditate, cook healthy meals, and get more sleep. I see this in a small proportion of patients. A larger group did worse with additional factors being worsening of headaches due to COVID and in a very small number, COVID vaccines.

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There is a new and surprising connection between postoperative nausea and vomiting (PONV) and migraines. It offers a very effective treatment that will relieve the suffering of tens of thousands of patients.

Many migraine patients tell me that they develop a severe migraine following surgery. Possible reasons include the stress of the operation, fasting before surgery, the effect of anesthetic drugs, pain medicines given after surgery, an awkward head position, and caffeine withdrawal. But some patients report severe nausea and vomiting that occurs without a headache.

PONV affects about 30% of all patients undergoing surgery under general anesthesia. Some patients develop intractable vomiting that does not respond to typical nausea medications even though there are more than a dozen such medications. This often requires hospital admission when surgery is done in an ambulatory (outpatient) setting. Admissions for PONV are more common than for surgical or cardiovascular complications. Intractable PONV can cause opening of the sutured wound, aspiration pneumonia, bleeding, and other complications.

It appears that patients who suffer from migraines or have had migraines in the past are more prone to develop intractable PONV. I learned about this last month while participating in a headache conference in Zurich. Dr. Leander Sakellaris, a Swiss anesthesiologist and pain specialist, told me about his Masters degree thesis on this topic. He allowed me to share its full text – MasterThesis-PONV.

His thesis describes ways to reduce the risk of PONV. If possible, ask for surgery to be done under regional and not general anesthesia. Ask if total intravenous anesthesia is an option. Avoid nitrous oxide, etomidate, thiopental and after surgery, opioid drugs. Good hydration during the operation is also helpful. I would also add a request for an intravenous (IV) infusion of magnesium. IV magnesium is a standard procedure after open heart surgery because it prevents irregular heart beats (arrhythmias), but it is not given after other types of surgery. Magnesium is depleted by physical and emotional stress and surgery induces a major stress response.

The most fascinating part of Dr. Sakellaris’ thesis is the description of eight patients he has encountered in his practice. They all developed intractable PONV but did not have a headache. However, they all had a history of migraines or headaches suggestive of migraines. After they failed to respond to the usual nausea medications, Dr. Skellaris gave them either an injection of sumatriptan or intranasal zolmitriptan. They all had a prompt and dramatic relief of their vomiting and were able to go home.

This should not be very surprising because abdominal migraines and cyclic vomiting syndrome, conditions without a headache that are considered to be migraine variants, also respond to triptans.

Dr. Sakellaris made an important discovery that deserves to be widely disseminated. Forty million Americans suffer from migraines, millions of Americans undergo surgery under general anesthesia, of whom 30% suffer from PONV. It is very likely that many thousands of patients with PONV who do not respond to standard therapies could be helped by triptans.

If you suffer from migraines or have had them in the past and are having an operation, you may want to bring with you an injection of sumatriptan. Outpatient surgery clinics may not have it while hospitals may take a long time to get it to you. I would discuss this with your surgeon and the anesthesiologist before surgery.

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With Swiss colleagues Drs. Caterina Podella, Livia Granata, and Reto Agosti at the headache conference held on November 4, 2021, in Zürich.
Dr. Podella presented a very comprehensive approach to the treatment of migraine headaches. Dr. Granata expertly covered the topic of cluster headaches. I spoke about the challenges of treating refractory migraine headaches and Dr. Agosti provided a lively and insightful discussion of all these topics.

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The influence of estrogen on migraines in women is well established – women often experience migraines before or during menstruation and ovulation and their migraines usually subside during pregnancy and menopause.

According to a new study published this month by Dutch researchers, men who suffer from migraines often have a deficiency of male hormones.

Gisela Terwindt and her collaborators evaluated a possible deficiency of androgens or male hormones in 534 men with migraine and 437 men with cluster headaches. These men were compared to 152 healthy controls. Two validated questionnaires were used to measure androgen deficiency scores. The researchers controlled for age, weight (BMI), smoking, and lifetime depression. They also measured four sexual symptoms (beard growth, morning erections, libido, and sexual potency). These four symptoms have been shown to differentiate between hormonal deficiency from anxiety and depression. They did not perform blood tests to measure hormone levels.

Patients reported more severe symptoms of clinical androgen deficiency compared with controls. Both patient groups were more likely to suffer from any of the specific sexual symptoms compared to controls (18% migraine, 21% cluster headache, 7% controls).

The findings in men with cluster headaches are not surprising. Prior reports have documented low testosterone levels in this population. A small study by Dr. Mark Stillman suggested that those cluster patients who have low testosterone levels could benefit from hormone replacement therapy.

There are also reports of low testosterone levels in men with chronic migraines but the connection is less established.

This study may prompt me to pay more attention to sexual dysfunction in men with chronic migraines. I may also start checking testosterone levels in such patients.

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