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Migraine in pregnancy

Researchers at a hospital in Northern India reported good results in treating New Daily Persistent Headache (NDPH) with repetitive transcranial magnetic stimulation (rTMS).

NDPH is a type of headache that begins suddenly and persists daily without specific features, distinct MRI presentation, or blood test abnormalities. It can present similarly to chronic migraines or chronic tension-type headaches. While published reports suggest NDPH is difficult to treat, this is often not the case. However, patients who do not respond to initial standard treatments may become discouraged.

The Indian researchers conducted a pilot study with 50 NDPH patients who received 10 Hz rTMS sessions on the left prefrontal cortex of the brain for three consecutive days. They found that after 4 weeks:

  • 70% of patients had at least a 50% reduction in headache severity

  • Patients gained an average of 11 headache-free days per month

  • 76% had significant improvements in headache-related disability

  • Depression and anxiety scores also improved significantly

The treatment was well-tolerated, with only minor side effects in a few patients. The benefits seemed especially pronounced in patients who had NDPH that resembled chronic migraine.

I never give the diagnosis of NDPH, but diagnose it as a condition it most resembles and treat the person with a wide variety of available options. Many respond. For those who do not, we offer rTMS, a procedure that uses magnetic fields to stimulate nerve cells in the brain. An electromagnetic coil device is placed against the scalp near the forehead. The coil painlessly delivers a magnetic pulse that stimulates the brain with the goal of reducing headache symptoms. The FDA has approved it for the treatment of depression, anxiety, and OCD. We use it for various neurological conditions, including headaches that do not respond to standard therapies. To treat migraines and other types of pain, we usually stimulate not only the left prefrontal cortex, as was done in this study, but also two additional sites that have been reported to help with pain and migraines. These additional sites are either the motor cortex or the occipital cortex, on both sides.

Sometimes, we obtain a functional magnetic resonance imaging (fMRI) scan to better target rTMS. fMRI is a research procedure that is not available commercially (and is not covered by insurance).

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Dr. Messoud Ashina of the Danish Headache Center led a group of European researchers in analyzing the efficacy of migraine medications for treating acute migraine attacks. Their paper published in the British Medical Journal, “Comparative effects of drug interventions for the acute management of migraine episodes in adults: systematic review and network meta-analysis”, looked at 137 randomised controlled trials comprising 89,445 participants allocated to one of 17 active interventions or placebo.

They concluded that “Overall, eletriptan, rizatriptan, sumatriptan, and zolmitriptan had the best profiles, and they were more efficacious than the recently marketed drugs lasmiditan, rimegepant, and ubrogepant.”

When I decided to specialize in treating headaches in 1987, the options for the treatment of acute migraine attacks were very limited. We had NSAIDs, like aspirin and ibuprofen, opioids (narcotics), and ergotamines. Now, we have a cornucopia of options – seven triptans (the first in this group, sumatriptan, was introduced in 1992), three gepants, and one ditan.

Triptans work on serotonin receptors, gepants affect CGRP, and ditan, lasmiditan (Reyvow) works on a different serotonin receptor than triptans.

Over more than 30 years, triptans have proven to be exceptionally safe and effective. In many countries, they are sold without a prescription. Since patents for these drugs have mostly expired, they have become inexpensive.

Gepants were introduced almost five years ago. Ubrogepant(Ubrelvy) and rimegepant (Nurtec) came out first, and more recently, a nasal spray of zavegepant (Zavzpret) was added to this group. They also appear effective and safe, although they have not withstood the test of time like the triptans. And, because they are still protected by patents, they are costly. I don’t think that the prices are too high – if companies cannot recoup literally billions of dollars it takes to get FDA approval, no new drugs will emerge.

It is good to have all these options available because triptans do not work for about 30-40% of patients. For these people, gepants can be life-saving.

In the US, many insurers insist that a patient tries one or two triptans first before they will agree to pay for the more expensive gepants.

In the analysis, eletriptan came out first. However, even though a generic version was introduced in 2017, the cost has not come down as much as for sumatriptan or rizatriptan. Generic sumatriptan can be bought for $.60 a pill, while eletriptan costs $2 a pill. Another important point is that, despite low cost, insurance companies will cover 6 to 12 tablets a month. Some patients don’t realize that if they need more than this amount each month, they could buy extra by paying out-of-pocket, provided their doctor gives them a prescription for a higher amount.

In the US, eletriptan is available in 20 mg and 40 mg strengths. In some European countries, they come in 80 mg strength. The point is that taking two 40 mg tablets at once is not dangerous.

Some patients report that generics do not work as well as branded drugs. Others find that generics made by different manufacturers differ in their efficacy. The manufacturer’s name is always listed on the pill bottle dispensed by the pharmacy. The reason for this discrepancy is not necessarily due to different amounts of the active drug but rather due to inactive ingredients that hold the pill together. Some may not dissolve as fast or as completely as others. This is another reason why taking a higher-than-recommended dose may be necessary.

Triptans are safer than most over-the-counter drugs, such as ibuprofen (Advil), naproxen (Aleve), or Excedrin. They are safer for your stomach, kidneys, and heart.

 

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Functional MRI (fMRI) studies have shown that people with migraines have altered functional connectivity and activation patterns in pain-processing brain regions like the insula, thalamus, somatosensory cortex, as well as visual cortex. Some patients also have changes in the default mode and salience networks involved in attention and stimulus processing.

A study published this month by Chinese researchers in the Journal of Headache and Pain reports on connectivity changes in people with vestibular migraines.

They found abnormal resting-state functional connectivity in brain regions involved in multi-sensory and autonomic processing as well as impaired ocular motor control, pain modulation, and emotional regulation.

Until now, there has been little practical application for fMRI findings. However, with the help of Omniscient Neurotechnology, we have just started using fMRI data to better target our treatment with transcranial magnetic stimulation (TMS). TMS applied to motor and visual cortices has been reported to help relieve migraine headaches. We have also found it effective in a significant proportion of patients who did not respond to various other treatments. We have not yet accumulated enough data to determine if fMRI-guided TMS treatment is superior to TMS administered over a predetermined set of targets.

The main obstacle to wider use of TMS in clinical practice is the cost. TMS is approved by the FDA and is covered by insurance for the treatment of anxiety and depression, but not migraines or pain. fMRI is an expensive research tool and is also not covered by insurance. Hopefully, the NIH and other research foundations will provide the funds needed to study this promising treatment.

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Neurologists frequently find themselves managing patients resistant to standard treatments due to limited proven therapies for many neurological conditions. Some patients cannot tolerate or have contraindications to medications, particularly for such common disabling conditions like migraine and chronic pain. 

One promising treatment is transcranial magnetic stimulation (TMS). It is a proven procedure for anxiety, depression, obsessive-compulsive disorder (OCD), smoking cessation, and acute migraines. TMS utilizes magnetic fields to stimulate nerve cells in the brain that are underactive or reduce the excitability of overactive cells. TMS can change the flow of information between different parts of the brain in various neurological conditions. Published reports show the potential benefit of TMS in fibromyalgia, neuropathic pain, cluster headaches, facial pain, trigeminal and other neuralgias, back pain, insomnia, memory disorders, tinnitus, post-concussion syndrome, post-traumatic stress disorder (PTSD), restless leg syndrome, and long COVID. The evidence for the efficacy of TMS for these neurological disorders, however, is still limited.

Single-pulse TMS is approved by the FDA for the acute treatment of migraines with aura. The patient uses a portable device during the aura phase to self-administer a single pulse of TMS to the back of the head. This can abort the attack. Repetitive TMS (rTMS) has been studied for the prevention of migraines and other types of pain. It appears effective, but compared to depression trials, migraine studies were relatively small and the FDA has not cleared rTMS for the treatment of migraines. This means that insurance companies are not likely to pay for this “off-label” use of TMS.

rTMS is generally considered safe and well-tolerated, with side effects typically mild and temporary, including scalp discomfort, headaches, and facial twitching. More serious side effects like seizures and mania are very rare. 

Before starting TMS, patients undergo a physical and mental health evaluation. The coil placement and dose are determined in the first session. During a TMS session, patients sit in a comfortable chair with earplugs. An electromagnetic coil is positioned near the scalp, delivering short magnetic pulses to specific brain regions involved in processing pain and other information. Patients feel and hear rapid tapping on their scalp that continues, on and off. Patients are awake and alert during the entire procedure. There are no limitations to activities before or after the treatment.

Treatment length varies from 20 to 45 minutes, depending on the stimulation pattern and number of sites stimulated. The frequency of treatments also varies – anywhere from daily for several weeks, to once a week. After the initial period of more frequent sessions, some patients require weekly or monthly sessions to maintain the effect. It may take a few weeks to see noticeable effects. 

TMS is a good choice for people who have not responded to multiple standard therapies, people who do not want to take drugs, those who also suffer from depression and anxiety, and pregnant women. Sufficient evidence suggests that TMS is as safe in children as it is in adults, with studies indicating its effectiveness in treating depression in adolescents.

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The annual course, “The Shifting Migraine Paradigm 2024” will be held February 15-17, 2024 at the Plaza San Antonio Hotel & Spa. This three-day conference offers an excellent update on the treatment of migraine and other headaches.

It is always an honor to be invited to speak at this event. The topic of my presentation is Supplements and Medical Foods.

 

 

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The thyroid function test is in the initial battery of blood tests we order on all our headache patients (along with RBC magnesium, vitamins D, B12, folate, and others). Having either an overactive or underactive thyroid is known to worsen migraine headaches.
A new study published by Indian researchers confirmed that treating an underactive thyroid improves headaches. The researchers studied 87 headache patients with a mild decrease in thyroid function. Half of them were prescribed thyroid medicine and the other half received a placebo. Correcting thyroid deficiency improved headache frequency, severity, and disability (MIDAS score) at three months of follow-up in the treatment group compared to the placebo group.
The conclusion was that it is logical to check thyroid function status in patients presenting with migraine headaches.
Thyroid function can sometimes decline precipitously and cause worsening of headaches without any other symptoms. This can happen after delivering a baby and the cause is often misinterpreted. Lack of sleep, stress, hormonal changes (female hormones, not thyroid hormone), occlusion of veins inside the head, and even stroke are suspected.  All those conditions can cause headaches after the delivery. But we should not forget to check the thyroid.
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Since the legalization of medical marijuana in New York in 2014, I have prescribed it to several hundred patients. My experience suggests that approximately one-third of my patients benefit from its use and continue to rely on it for their medical needs. Some have reported relief from symptoms such as nausea and anxiety, often associated with migraines, while others find it highly effective in aiding sleep. Additionally, there are patients who have reported significant pain relief.

It is possible that the relatively low response rate I see in my patients is due to the fact that I reserve medical marijuana for those patients who do not respond to multiple drugs.

At the recent meeting of the International Headache Society, Dr. Nathaniel Schuster and his colleagues presented a study titled “Vaporized cannabis versus placebo for the acute treatment of migraine: a randomized, double-blind, placebo-controlled, crossover trial.” This study aimed to investigate the potential of medical marijuana in alleviating pain and associated migraine symptoms.

In this study, participants were instructed to treat moderate-to-severe migraine attacks within four hours of onset using vaporized cannabis flower. They were asked to treat up to four separate migraine attacks, using vaporized cannabis with different compositions: 1) THC-dominant (6% THC), 2) CBD-dominant (11% CBD), 3) THC/CBD mix (6% THC/11% CBD), and 4) placebo cannabis, with the order randomized and double-blinded.

Out of the 92 participants enrolled, 71 treated at least one migraine attack. Two hours after vaporization, the THC/CBD mix outperformed the placebo in achieving pain relief (69% vs. 48%), pain freedom (36% vs. 16%), and freedom from the most bothersome symptoms, such as nausea, photophobia, or phonophobia (62% vs. 36%). The THC-dominant option was superior to the placebo for pain relief at 2 hours (71% vs. 48%) but was not significantly different from the placebo regarding pain freedom or freedom from the most bothersome symptoms. The CBD-dominant option did not significantly differ from the placebo in terms of pain relief, pain freedom, or freedom from the most bothersome symptoms. The most common side effects reported were sleepiness, followed by euphoria, with no serious adverse events observed.

In conclusion, the authors of the study found that the acute treatment of migraine with a vaporized THC/CBD mix (6% THC/11% CBD) was superior to the placebo in terms of pain relief, pain freedom, and freedom from the most bothersome symptoms at the 2-hour mark.

This study has significant practical implications. In the past, I would leave the choice of products to the licensed pharmacist at the dispensary, while advising patients that finding the right combination is often a trial-and-error process. However, now, I will be better equipped to advise my patients on the most suitable type of medical marijuana for their specific needs based on the findings of this study.

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Because migraine is fundamentally a brain disorder, the involvement of physical therapists in its treatment might seem unnecessary. However, their contribution can be profoundly impactful, provided they have a keen interest in the nuances of migraine care.

One such physical therapist to whom I refer patients, Pete Schultz, just co-wrote an article, A Multimodal Conservative Approach to Treating Migraine: A Physical Therapist’s Perspective.

This article shows how experienced physical therapists approach migraine patients. They usually perform a very thorough examination and they can sometimes detect a serious problem that was missed by a physician.

The physical therapist often discovers general weakness, muscle tension, poor posture, diminished endurance, neck pain, teeth clenching, visual symptoms, dizziness, poor balance and coordination and high stress levels.

The interventions may include exercise directed at strengthening neck and upper back muscles, manual therapy, general conditioning exercise, biofeedback and mindfulness techniques, and vestibular therapy.

There is a wealth of data on the therapeutic effect of exercise in migraine patients. Interestingly, weight training seems to be more effective in the prevention of migraines than aerobic exercise.

Vestibular symptoms, such as dizziness and unsteadiness, are very common and are highly responsive to vestibular therapy.

Biofeedback is typically done by mental health professionals, but also by physical therapists. Over 100 clinical trials have been performed utilizing biofeedback in the treatment of headaches. The consensus is that this is a very effective technique.

An additional benefit that physical therapists can provide is what psychologist call a shift in locus of control, from internal to external. This means that instead of feeling like a victim of external uncontrollable circumstances, people acquire agency and cam actively do things to help themselves. This shift has been consistently shown to increase the efficacy of headache and pain treatment.

 

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A recently published study suggests that valproic acid (Depakene) given intravenously in an emergency room can relieve migraine headaches in children. The researchers also showed that giving these children an oral version of this drug, divalproex sodium (Depakote), does not reduce the frequency of future migraine attacks. 

Divalproex sodium was first approved by the FDA in 1983 for the treatment of epilepsy. Subsequently, it was also approved for the treatment of mania and for the prevention of migraine headaches. Notably, the FDA-approved label does not place any age limit on the use of this drug. It took years to discover all the risks associated with this medication. In rare instances, the drug may lead to liver failure and severe pancreatitis, both of which can be fatal. Moreover, divalproex sodium can result in significant congenital malformations, as well as diminished IQ scores and neurodevelopmental disorders when the fetus is exposed to the drug in utero. It is strictly contraindicated in pregnant women. Women of childbearing age must use effective contraception. Divalproex can also cause many other less dangerous but unpleasant side effects.

With all this in mind, why would anyone want to take this drug? It is certainly not on the list of my top 20 or 30 drugs for the prevention of migraines. I do, however, have several patients whose migraines did not respond to many drugs but are significantly improved with divalproex sodium. Such patients must have proper monitoring with regular blood tests.

We do occasionally give intravenous valproic acid in the office but only if 5 or 6 other acute treatments fail to stop a severe persistent migraine. It works in about half of our patients. I am even more reluctant to give this drug to children.

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Botox injections is arguably the safest and most effective preventive treatment for migraine headaches. There have been cases of pregnant women receiving Botox for various medical and cosmetic reasons, and no evidence suggests that the fetus gets harmed during this treatment. The botulinum toxin molecule is too large to cross the placenta and enter the circulation of the fetus, which further supports its safety during pregnancy.

An analysis of pregnancy outcomes after onabotulinumtoxinA exposure over a 29-year period was conducted to gain more insights into the safety of the treatment during pregnancy. The researchers examined data from the Allergan Global Safety Database from 1990 to 2018, focusing on pregnant women or those who became pregnant within three months of receiving onabotulinumtoxinA treatment. They analyzed the outcomes of these pregnancies to estimate the prevalence of birth defects in live births.

Out of 913 pregnancies, the study considered 397 with known outcomes. The majority of the mothers were 35 years or older, and most of the onabotulinumtoxinA exposures occurred before conception or during the first trimester of pregnancy. Among the 197 fetuses from 195 pregnancies, there were 152 live births and 45 fetal losses (including spontaneous and elective abortions). Four of the 152 live births had abnormal outcomes, with one major birth defect, two minor fetal defects, and one birth complication. The overall prevalence of fetal defects in live births was 2.6%, with a prevalence of 0.7% for major defects, similar to the rates seen in the general population. Among the cases with known exposure times, one birth defect occurred with preconception exposure and two with first-trimester exposure.

While the study has some limitations due to the nature of the data collected, the results indicate that the rate of major birth defects in live births exposed to onabotulinumtoxinA is consistent with the rates seen in the general population. However, it is important to note that there is limited data available for exposure during the second and third trimesters of pregnancy. Nevertheless, this updated and expanded analysis provides valuable real-world evidence for healthcare providers and their patients when considering Botox treatment during pregnancy.

I’ve treated more than a dozen pregnant women in my 30 years of using Botox for migraines. Some of them received Botox during more than one pregnancy. Some pregnant women sought Botox treatment specifically because they preferred to avoid taking any medications during pregnancy. Their decision was justified. When it comes to migraine drugs, including over-the-counter pain medications, they carry a higher likelihood of causing harm during pregnancy.

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Researchers at the Cleveland Clinic investigated the risk of stroke associated with different estrogen doses in oral contraceptives (OCP) for individuals with migraines. The results of their study were recently published in the journal of the American Headache Society, Headache.

The overall stroke risk among OCP users in this study was low. Out of the 203,853 women aged 18-55 who used OCPs, 127 were confirmed to have had a stroke. The case group had a higher proportion of individuals diagnosed with migraines (34/127, 26.8%) compared to a control group of 635 women (109/635, 17.2%; p = 0.011). The risk of stroke was higher among those using OCPs with 30 mcg or more of estrogen compared to those using OCPs with less than 30 mcg. Having a personal history of migraines increased the likelihood of stroke compared to those without migraines. There was no significant increase in stroke risk among those with migraine with aura, but migraine without aura did increase the risk.

Interestingly, previous studies have suggested the opposite—that migraine with aura carries a higher stroke risk compared to migraine without aura. The researchers speculate that this discrepancy could be because patients with migraine with aura are rarely prescribed OCPs, and the number of such patients in this study was small.

Traditionally, young and healthy women diagnosed with migraine with aura have been advised against using estrogen contraceptives due to concerns about increased stroke risk compared to those without aura. However, the risk of unintended pregnancies should be weighed against the risk of a stroke. The authors emphasize the need for proper patient education and shared decision-making when it comes to starting contraceptives in women with a history of migraines, including those without aura. OCP formulations with less than 30 mcg of estrogen are preferred to minimize the risk of stroke.

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