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Chronic migraine

Modern technology may help manage or even prevent pain before it becomes chronic. A recent study exploring the effects of repetitive transcranial magnetic stimulation (rTMS) on pain sensitivity offers some intriguing insights.

What is rTMS?

rTMS is a non-invasive method of brain stimulation. It involves sending magnetic pulses to specific areas of the brain through a coil placed on the scalp. This technique has been used to treat conditions like depression and chronic pain, but researchers are now looking at its potential to prevent pain. We used rTMS at the New York Headache Center to treat chronic migraine, other pain and neurological conditions that do not respond to usual treatment.

In a controlled experiment, researchers led by Nahian Chowdhury examined the role of rTMS in reducing future pain in healthy volunteers. The results were published in the latest issue of Pain, a journal of the International Association for the Study of Pain.

The subjects were divided into two groups:

Active rTMS Group: Received high-frequency rTMS to the area of the brain responsible for hand movements.

Sham rTMS Group: Received a fake treatment for comparison.

Both groups were then given an injection of nerve growth factor (NGF) into their jaw muscles, which causes prolonged pain similar to temporomandibular disorders (TMD), a condition causing jaw pain and dysfunction.

Results:

Pain Reduction: Participants who received active rTMS reported significantly less pain when chewing or yawning than the sham group. This effect was more pronounced in the early stages after the injection but persisted for days and weeks.

Brain Activity: The study found an increase in what’s known as peak alpha frequency (PAF) after rTMS, which is linked to lower pain sensitivity.

What Does This Mean for Pain Management?

Preventive Potential: This research suggests that rTMS could be used prophylactically to reduce pain sensitivity when pain is expected, like before surgery.

Future Directions: While promising, this study opens the door to further research into how rTMS can be optimized for pain control, potentially exploring different frequencies, duration, and areas of stimulation.

Pre-Surgery: rTMS might be used to reduce postoperative pain, potentially preventing the transition to chronic pain.

Chronic Pain Management: For those already dealing with chronic pain, understanding how brain activity changes with rTMS could lead to more effective treatments.

Conclusion

While we are still in the early stages, this study of rTMS offers hope for pain sufferers. It suggests a future where we might not only treat pain more effectively but also prevent it from becoming a long-term problem. This could revolutionize our approach to pain management, making it less about reducing and enduring pain and more about preventing it from taking root in the first place.

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It’s an honor to have contributed, alongside Andrew Blumenfeld and Sait Ashina, a chapter on Botox injections to the upcoming textbook Headache and Facial Pain Medicine. Edited by Sait Ashina of Harvard Medical School and published by McGraw Hill, the book is set for release in 2025 but is already available on Amazon.

The book includes chapters on Primary Headaches, Secondary Headaches, Facial Pain and Cranial Neuralgias, Special Treatments and Procedures, Special Populations, and Special Topics. It is an excellent textbook for health care providers.

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“Dr. Mauskop,
Congratulations on hitting a new milestone – over 3800 citations of your articles! This places you in the top 5% for citations within the Doximity community.”
Some of the most cited articles:
– Intravenous Magnesium Sulphate Relieves Migraine Attacks in Patients with Low Serum Ionized Magnesium Levels: A Pilot Study
– Botulinum toxin type A for the prophylaxis of chronic daily headache: Subgroup analysis of patients not receiving other prophylactic medications: A randomized double-blind, placebo-controlled study
– Clinical Guidelines for the Use of Chronic Opioid Therapy in Chronic Noncancer Pain
– Effect of noninvasive vagus nerve stimulation on acute migraine: an open-label pilot study
– Foods and supplements in the management of migraine headaches.
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Hemicrania continua, a rare but severe headache condition, literally means “continuous one-sided headache” in Latin. This chronic condition manifests as an intense, unrelenting pain concentrated on one side of the head, typically around the eye area. It is more common in women.

The condition often presents with distinctive features beyond the constant one-sided pain. Patients frequently experience:

  • Redness and tearing of the affected eye

  • Nasal congestion and runny nose

  • Forehead and facial sweating

  • Eyelid swelling

  • Pupil size changes

  • Restlessness or agitation

The diagnosis of hemicrania continua can be particularly challenging, especially when the only symptom is a one-sided headache. Doctors often misdiagnose it as migraine or tension headache because of its rarity and overlap with other headache types.

What makes hemicrania continua unique is its remarkable response to indomethacin, a powerful non-steroidal anti-inflammatory drug (NSAID). The response to this medication is so dramatic that hemicrania continua is one of two headache types that are called indomethacin-sensitive headaches.

While indomethacin is highly effective, some patients may experience stomach-related side effects. For those who cannot tolerate indomethacin, several alternatives exist:

  • Other NSAIDs (though generally less effective)

  • Boswellia, an herbal supplement with anti-inflammatory properties

  • Botox injections

Chronic paroxysmal hemicrania shares features with hemicrania continua but differs in its pattern. It causes more intense pain attacks lasting minutes but occurring many times throughout the day. Like hemicrania continua, it also responds extremely well to indomethacin.

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If you’re one of the millions of people who suffer from migraines, you might be worried about the long-term effects on your brain. Recent studies have suggested that people with migraines might be at higher risk for structural brain changes, such as damage to small vessels in the brain and shrinkage of the brain or brain atrophy.

A recent study published in Cephalalgia by Dutch researchers examined the connection between migraines and brain health in over 4,900 middle-aged and elderly people. The researchers used magnetic resonance imaging (MRI) to study the brains of the participants and assess any structural changes.

The study found that people with migraines were not any more likely to have structural brain changes than those without migraines. There were no significant differences between the two groups in terms of:

  • Total brain volume

  • Grey matter volume

  • White matter volume

  • White matter hyperintensity volume (a marker for small vessel disease)

  • Presence of lacunes (tiny holes in the brain)

  • Presence of cerebral microbleeds (small bleeds in the brain)

This study suggests that having migraines may not increase your risk of developing structural brain changes as you age. This is reassuring news for people who suffer from migraines and are concerned about the long-term effects on their brain health.

 

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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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Two sets of “designer drugs” have been developed based on our understanding of the neurobiology of migraines. The first, sumatriptan (Imitrex), introduced in 1992, was the pioneer in a class of seven triptan drugs, all targeting serotonin mechanisms. Erenumab (Aimovig), which targets the CGRP (calcitonin gene-related peptide) mechanism, was approved by the FDA in 2018. This class now includes four injectable, three oral, and one nasal drug. Additionally, many older drugs, although not specifically developed for migraine treatment, have proven effective for some patients. Despite these numerous options, a significant minority of patients do not respond to any of these treatments.

This is why the development of drugs targeting different parts of the migraine cascade is so promising. Danish neurologists, led by Dr. Mesoud Ashina, have published results from a phase 2 double-blind study of a new drug that blocks PACAP (pituitary adenylate cyclase-activating peptide).

In this study, patients were divided into two groups, receiving an infusion of a placebo or two different doses of the active drug, currently known as Lu AG09222, developed by the Danish company Lundbeck. In the final analysis, the reduction in migraine days was compared between 94 patients who received a placebo and 97 patients who received the higher dose of the active drug. The higher dose significantly reduced the number of migraine days in the month following the infusion (6.2 vs. 4.2 days reduction). The side effects reported were mild and infrequent.

Phase 2 studies are relatively small and short in duration. The FDA typically requires two large parallel studies involving a total of 1,000 or more patients before considering approval. Therefore, even if Lu AG09222 is found to be safe and effective, it may not receive approval for another 2-3 years.

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Long COVID, also known as post-COVID conditions, can present with a wide range of symptoms that persist for weeks or months after the initial COVID-19 infection. The most common symptoms of long COVID include:

Neurological Symptoms

  • Headaches
  • Difficulty thinking or concentrating, often referred to as “brain fog”
  • Memory problems
  • Changes in smell or taste

Psychological Symptoms

  • Depression or anxiety
  • Mood changes

Other Symptoms

  • Fatigue or tiredness that interferes with daily life
  • Shortness of breath or difficulty breathing
  • Cough
  • Chest pain or heart palpitations
  • Sleep problems
  • Dizziness when standing up (orthostatic hypotension)
  • Joint or muscle pain
  • Fever
  • Stomach pain or other gastrointestinal issues
  • Changes in menstrual cycles

There is evidence of persistent inflammation in people with long COVID. This inflammation of blood vessels, brain tissues, and other organs is likely the cause of all of the above symptoms.

Receiving a COVID vaccination may prolong the symptoms of long-term COVID-19 in people who have already contracted COVID and now suffer from long COVID. However, vaccines seem to reduce the risk of severe COVID and long COVID.

Unfortunately, we do not have any proven therapies for long COVID. However, it is very important to make sure that nutritional deficiencies do not contribute to long COVID symptoms. I often find a deficiency of vitamin B12 and other B vitamins, vitamin D, magnesium, CoQ10, omega-3 fatty acids, zinc, and others. I recommend looking at your test results yourself since doctors may glance at the report and tell you everything is fine if nothing is flagged. The normal ranges for vitamins are too wide, and if you are at the bottom of the normal range, you are probably deficient. For example, vitamin B12 levels are considered normal between 200 and 1,200. Most neurologists will tell you that your level should be above 500. The same applies to RBC magnesium level – normal is 4.0 to 6.4, but you need to be above 5. Vitamin D should be well above 40, while 30 is still considered normal.

Another supplement I often recommend is NAC. A small study by Yale neurologists showed that 600 mg of NAC improved working memory, concentration, and executive functions. NAC helps the body produce glutathione, an important antioxidant. We sometimes give glutathione infusions along with other vitamins.

Supplements that reduce inflammation include ginger and turmeric extracts.

For brain fog and other neurological symptoms, we have had some success with transcranial magnetic stimulation (TMS). Other neurostimulation methods, such as tDCS, are also worth trying.

Some patients benefit from intravenous infusion of immune globulin, which is approved for some types of neuropathies.

Low-dose naltrexone (LDN) may also help, but no studies prove this.

Probiotics can help people with gastrointestinal symptoms.

Stimulants can be tried to treat fatigue and brain fog. They can also help with depression.

For headaches, we often give Botox injections.

Depression can be treated with antidepressants or TMS.

Some people respond well to physical therapy, acupuncture, herbs, meditation, cognitive-behavioral therapy, and other mind-body techniques.

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The FDA approved transcranial magnetic stimulation (TMS) to treat anxiety, depression, and OCD about 15 years ago. Most insurers cover this treatment. However, it remains highly underutilized.

A study just published by Dutch researchers in Psychiatry Online compared TMS with a third antidepressant in people who did not respond well to two different antidepressants.

Both treatments were combined with psychotherapy.

  • 89 people with depression who hadn’t improved with at least two previous treatments took part.

  • They were randomly assigned to either TMS or a new antidepressant.

  • The treatment lasted eight weeks.

  • TMS involved 25 sessions of magnetic stimulation.

  • The medication group switched to a new antidepressant following standard guidelines.

The primary outcome measure was the degree of improvement in depression symptoms.

TMS was more effective than switching medications. More people responded well to MS (38% vs 15%) and more people’s depression went into remission with TMS (27% vs 5%).

TMS was better at improving symptoms of anxiety and lack of enjoyment (anhedonia)

Both treatments were equally effective for improving sleep, overthinking, and negative thought patterns. People’s expectations about their treatment were linked to how much their depression improved.

In conclusion, for people with depression that hasn’t responded well to a couple of medication attempts, TMS might be a more effective option than trying another antidepressant. The study also suggests that the choice between TMS and medication might depend on which specific symptoms a person struggles with most.

We started using TMS for people with migraine headaches if they do not respond to multiple standard therapies. About half of these patients respond well. However, we do not have large controlled trials to confirm that TMS effectively treats migraines.

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The use of focused ultrasound to treat brain disorders was one of the topics discussed at the 2024 NYC Neuromodulation Conference in NYC.

Coincidentally, a study on this topic was published last month by Jan Kubanek and his colleagues in Pain, the journal of the International Association for the Study of Pain: “Noninvasive targeted modulation of pain circuits with focused ultrasonic waves”.

Researchers developed a technique that targets the anterior cingulate cortex, a deep brain region involved in processing pain. By using focused ultrasound, this region can be modulated without surgery. This breakthrough has the potential to revolutionize pain management.

Twenty patients with chronic pain participated in a randomized crossover trial. They received two 40-minute sessions of either active or sham stimulation and were monitored for one week. The results were remarkable:

  • 60% of patients experienced a significant reduction in pain on day 1 and day 7 after active stimulation.
  • Sham stimulation only benefited 15% and 20% of patients, respectively.
  • Active stimulation reduced pain by 60.0% immediately after the intervention and by 43.0% and 33.0% on days 1 and 7.
  • Sham stimulation only reduced pain by 14.4%, 12.3%, and 6.6% on the same days.

The stimulation was well tolerated and the side effects were mild and resolved within 24 hours.

Since we have been using transcranial magnetic stimulation (TMS) to treat refractory migraines and other neurological conditions, it was good to read this part of the authors’ conclusion:

“The ultrasonic intervention is conceptually related to TMS applied to the motor cortex, which can provide improvements in chronic pain in certain groups of patients. The key difference is that ultrasonic waves can directly modulate the deep brain regions involved in chronic pain, including the anterior cingulate cortex. Transcranial magnetic stimulation is believed to modulate deep brain regions only indirectly, which may contribute to its variable response and the need for frequent re-administrations. Nonetheless, the effects of both modalities may be complementary, and their combined application may provide stronger effects than either approach alone.”

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The diagnosis of migraine still relies on the patient’s description of symptoms. We do not have an objective test to confirm the diagnosis.

Several studies using functional MRI (fMRI) attempted to identify people with migraines. A new study published by Korean doctors in The Journal of Headache and Pain used a different imaging technique to achieve this goal.

The researchers used diffusion MRI, a technique that focuses on the movement of water molecules within the brain’s tissues (fMRI measures blood flow to different areas of the brain). It is particularly useful for mapping the brain’s white matter tracts, which are the pathways that connect different brain regions.

47 patients with migraine were compared to 41 healthy controls

Significant differences were found in brain regions such as the orbitofrontal cortex, temporal pole, and sensory/motor areas.

Changes in connections between deeper brain structures (like the amygdala, accumbens, and caudate nuclei) were also noted.

Using machine learning, the researchers could distinguish between migraine patients and healthy individuals based on these brain connectivity features.

Hopefully, larger studies and easier access to advanced imaging techniques may eventually lead to an objective test of migraines. More importantly, identifying specific connectivity patterns may lead to more individualized treatments. These could be treatments with pharmaceuticals or neurostimulation techniques such as transcranial magnetic stimulation (TMS), which we use in our clinic.

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