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Chronic migraine

Athletes have been using creatine supplementation for over 30 years. It seems to improve the energy supply to muscle tissues and increase fat-free mass. Creatine also supplies energy to nerve cells in the brain. Taking a creatine supplement increases the levels of creatine in muscles and the brain.

A review of six studies suggested that creatine improves short-term memory, intelligence, and reasoning. Creatine did not improve any cognitive abilities in young people. Vegetarians benefited more than non-vegetarians in memory tasks.

A study by Taiwanese researchers published in Cephalalgia showed reduced creatine levels in the thalamus (the pain-processing area in the brain) in patients with medication-overuse headaches.

Greek doctors published a report, Prevention of traumatic headache, dizziness and fatigue with creatine administration. A pilot study. They studied 39 patients who sustained a severe traumatic brain injury. There were 19 patients in the control group and 20 in the active group. The active group was given 0.4 g/kg of creatine. Treatment was administered within 4 hours of injury and was continued for 6 months. This treatment improved the duration of post-traumatic loss of memory, the duration of being on a respirator, and the duration of stay in an intensive care unit. They also showed improvement in headaches, dizziness, and fatigue. No side effects were reported.

Some studies suggest that creatine can improve bone health. Here is what WebMD says about creatine:

“While most people get low amounts of creatine by eating seafood and red meat, larger amounts are found in synthetic creatine supplements. Your pancreas and kidneys can also make around 1 gram of creatine each day. Creatine is one of your body’s natural energy sources.

Nearly 95% of the creatine in your body is stored in your skeletal muscles and is used during physical activity. As a dietary supplement, creatine is commonly used to improve exercise performance in athletes and older adults.”

There is not enough evidence to routinely recommend creatine for the treatment of migraine headaches. I do, however, recommend to my older patients taking 5 to 7  grams of creatine an hour before or after exercise.  I am 67 and do take it when I exercise.

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Candesartan ((Atacand) is a blood pressure medication in the class of angiotensin receptor blockers (ARBs). A recently published study involving 86 patients confirmed that candesartan can improve migraines. This was not a double-blind but rather an observational study, meaning that the results were not as reliable. However, the study is worth publicizing since candesartan is often overlooked as an effective migraine drug.

Here is more about candesartan from my previous post:

Candesartan was first shown to work for the prevention of migraine headaches in a 60-patient Norwegian trial published in JAMA in 2003. This was a double-blind crossover trial, which means that half of the patients were first placed on a placebo and then switched to candesartan and the second group started on candesartan and then were switched to placebo. This trial showed that when compared to placebo, 16 mg of candesartan resulted in a very significant reduction in mean number of days with headache, hours with headache, days with migraine, hours with migraine, headache severity index, level of disability, and days of sick leave. Candesartan was very well tolerated – there was no difference in side effects in patients taking the drug and those taking the placebo.

In another trial, the researchers compared candesartan to placebo as well as to propranolol, which is an FDA-approved blood pressure drug for the prevention of migraines. This trial in 72 migraine sufferers compared 16 mg of candesartan with placebo and 160 mg of propranolol. Candesartan and propranolol were equally effective in reducing migraine days per month and both were significantly more effective than placebo.

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A new study from Mayo Clinic researchers, published in The Journal of Headache and Pain, has examined the brain changes associated with acute post-traumatic headaches (PTH). These headaches can occur after a head injury or trauma and can be debilitating. The study involved 60 participants with acute PTH and 60 age-matched healthy controls. Using functional MRI (fMRI), the researchers found two key differences in the brains of PTH patients compared to healthy individuals.

Increased Iron Accumulation in Specific Brain Regions

First, the PTH patients showed higher levels of iron deposition in two brain areas: the left posterior cingulate and the bilateral cuneus regions. These areas are involved in various functions, including pain processing, attention, and visual processing. The accumulation of iron in these regions may disrupt normal brain function and contribute to the development and persistence of post-traumatic headaches.

Abnormal Functional Connectivity Patterns

Secondly, the researchers observed stronger functional connectivity between the bilateral cuneus (the visual processing area) and the right cerebellum (a region involved in motor control and coordination, and other functions) in PTH patients compared to healthy controls. Functional connectivity refers to the communication and synchronization between different brain regions. The abnormal connectivity patterns seen in PTH patients suggest disruptions in the brain networks responsible for processing sensory information, including pain signals.

Implications for Targeted Therapy

While these findings may have lacked utility in the past, they now have important implications for the treatment of post-traumatic headaches. We have been treating patients with repetitive transcranial magnetic stimulation (rTMS), a non-invasive technique that can modulate brain activity in specific regions. By stimulating the areas with abnormal connectivity, rTMS may help restore normal brain function and alleviate headache symptoms and other neurological and psychiatric symptoms. When possible, we perform fMRI scans on individual patients to identify the specific brain regions involved in their headache disorder. However, fMRI is still only a research tool, and when individual fMRI data is not available, studies like this one provide information on common brain changes associated with post-traumatic headaches that can be targeted with TMS.

 

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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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Several studies have suggested that fish oil helps prevent migraine headaches. A new clinical trial by Taiwanese doctors provides the strongest evidence for this effect to date. The paper, A 12-week randomized double-blind clinical trial of eicosapentaenoic acid intervention in episodic migraine” was published this month in the journal Brain, Behavior, and Immunity.

Unlike previous studies, this one used a high dose of one of the two omega-3 fatty acids found in fish oil, eicosapentaenoic acid, or EPA. 70 people with episodic migraine participated in a 12-week trial.

One group of 35 people took 2 grams of fish oil daily, which contained 1.8 grams of EPA. The other group of 35 people took a placebo of 2 grams of soybean oil daily. The researchers tracked several measures related to migraine frequency, severity, disability, anxiety/depression, quality of life, and sleep quality before and after the 12 weeks. The results showed that the EPA group did significantly better than the placebo group on multiple measures:

 – They had 4.4 fewer monthly migraine days on average compared to 0.6 fewer days in the placebo group.

– They used acute migraine medication 1.3 fewer days compared to 0.1 more days in the placebo group.

– Their headache severity scores improved more than the placebo group.

– Their disability scores related to migraine improved more.

– Their anxiety and depression scores improved more.

– Their migraine-specific quality of life scores improved more.

Notably, women seemed to particularly benefit from taking the high-dose EPA supplement. Overall, the high dose of EPA from fish oil was able to significantly reduce migraine frequency and severity, improve psychological symptoms, and boost the quality of life for these episodic migraine patients over the 12 weeks. No major side effects were seen.

The cheapest and the highest quality product that will give you such a high amount of EPA is a prescription drug, icosapent ethyl (Vascepa). Most insurers will not cover it for migraines but a 60-day supply (120 capsules) will cost you $77, according to GoodRx.com. You do need a doctor to prescribe it to you.

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A new study just published in Neurology showed that people taking proton pump inhibitors (PPIs) such as omeprazole (Prilosec) and esomeprazole (Nexium) have a 70% higher risk of having migraines or severe headaches. The risk was 40% higher with the use of H2 blockers such as famotidine (Pepcid) and 30% higher in those taking generic antacids.

The study analyzed data from 11,818 participants out of 31,127 in the National Health and Nutrition Examination Survey who were taking acid-suppressing drugs. Interestingly, those on H2 blockers had a higher migraine risk if they also had a higher intake of magnesium, though this finding was based on only 75 H2 blocker users, making it potentially unreliable.

The likely cause of the association between acid-suppressing drugs and headaches is the previously documented decrease in absorption of magnesium, vitamin B12, and other nutrients. PPIs have been also found to increase the risk of dementia.

These acid-suppressing drugs are available without a prescription and people assume that they are safe. They are indeed safe when used for short periods of time. Once a person starts taking PPIs, they are very difficult to stop because stopping them often leads to a rebound of acid production. This sometimes makes heartburn worse than before a PPI was started. One way to try to stop them is to switch to an H2 blocker and then, to an antacid such as Gaviscon or Rolaids.

For those who require long-term PPI use, supplementing with magnesium, sublingual vitamin B12, and a multivitamin may help mitigate potential nutrient deficiencies. Vitamin B12 is often poorly absorbed and getting a monthly injection is more reliable. Some of our migraine patients, even some who are not on acid-suppressing drugs, also require monthly infusions of magnesium.

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Nolan Williams has been at the forefront of developing breakthrough TMS protocols for the treatment of depression and other psychiatric indications. It was very stimulating and informative to discuss techniques, protocols, indications, and research into TMS for various neurological and psychiatric indications with the members of Nolan Williams’ lab Greg Sahlem and Ika Kaloiani. Thank you for sharing your knowledge.

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I will be speaking on nutritional supplements for migraines and an update on triptans on April 20, 2024.

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Repetitive transcranial magnetic stimulation (rTMS) is approved by the FDA for the treatment of depression and anxiety. We have been using it to treat migraine headaches and other neurological conditions that are not responsive to standard therapies. Improvement in headaches and pain may be at least in part due to improvement in depression. However, additional mechanisms play a role since we see patients who are not depressed but whose pain improves with rTMS.

A new study by Chinese and Australian researchers published in Pain suggests that opioid mechanisms (endorphins, encephalin, and other peptides) may underlie the mechanism of pain relief produced by rTMS.

This was a double-blind, placebo-controlled study. 45 healthy participants were randomized into 3 groups: one receiving rTMS over the primary motor cortex (M), dorsolateral prefrontal cortex (DLPFC), or sham stimulation. Experimental pain was induced by applying capsaicin (hot pepper extract) over the skin of the right hand followed by application of heat.

Participants received intravenous naloxone (an opioid receptor antagonist) or saline before the first rTMS session to block or allow opioid effects, respectively. After 90 minutes to allow naloxone metabolism, participants received a second rTMS session.

For the M1 group, naloxone abolished the analgesic effects of the first rTMS session compared to saline. Pain relief returned in the second session after naloxone was washed out of the body. For the DLPFC group, only the second prolonged rTMS session induced significant analgesia in the saline condition compared to naloxone. rTMS over M1 selectively increased plasma ?-endorphin levels, while rTMS over DLPFC increased encephalin levels.

The results suggest that opioid mechanisms mediate rTMS-induced analgesia. The specific opioid peptides and rTMS dosage requirements differ between M1 and DLPFC stimulation.

However, these results are far from definitive. The study was small and the study protocol was complicated (e.g. using a double dose of rTMS to DLPFC), which increases the likelihood of an error. Also, these results apply to conditions of acute pain. In patients with chronic pain and headaches, rTMS likely provides relief by improving network connectivity between different parts of the brain.

 

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A recent national survey called the “Harris Poll Migraine Report Card” provides insight into the profound impact migraine has on people’s lives, especially those dealing with frequent attacks and high acute medication use. The survey compared those currently experiencing high-frequency migraine (8 or more attack days per month) and using acute medication on 10 or more days per month, to those who previously had this pattern but now have reduced attack frequency and medication use.

Most respondents were first diagnosed with migraine or headache disorders in their mid-20s. However, despite meeting criteria for migraine, one-third did not self-identify as having migraine disease. This underscores how migraine is still underrecognized and misdiagnosed, with people often being mislabeled with terms like “stress headache.”

Regardless of diagnosis, the burden was clear – over 50% reported a negative impact on their overall quality of life. What’s more, at least half had experienced anxiety or depression, with almost half to over half saying migraine negatively affected their mental/emotional health. These findings align with prior research showing a significant burden can start at just 4 monthly migraine days.

In an attempt to improve their condition, most made lifestyle changes like stress management, limiting caffeine and improving diet. However, their treatment choices differed – those with more frequent migraine were more likely to use newer acute treatments like gepants, diclofenac and dihydroergotamine compared to the other group using more NSAIDs, triptans and ergotamines. The high-frequency group was also more inclined to try non-pharmacological options like supplements, marijuana, massage and physical therapy.

The use of prophylactic medications was low in both groups – about 15%. There are several potential reasons including lack of access to neurologists or even primary care doctors, lack of efficacy and side effects of existing drugs, and clinicians not encouraging the use of preventive medications.

The difference between these two groups could at least in part relate to the older age of the previous high-frequency group (mean age, 47 years vs 41), as age-related improvement can occur over time.

Interestingly, the high-frequency group had poorer optimization of their current acute treatments compared to those who previously experienced high frequency but reduced their attack frequency.

This brings the controversial issue of acute medication overuse into focus – does the suboptimal acute treatment lead to frequent use of medications, rather than the current widely accepted dogma that postulates that frequent use leads to more frequent headaches?

There is evidence that caffeine and opioid analgesics make headaches worse. The evidence for triptans and NSAIDs is based purely on correlational studies. Yes, I occasionally see patients improve when they stop or reduce their intake of NSAIDs or triptans. More often improvement comes from instituting effective preventive therapies along with lifestyle changes. NSAIDs have been proven to be effective for the prevention of migraine attacks and I have dozens of patients whose migraines are well-controlled with daily prophylactic or acute use of triptans. The safety of triptans is greater than that of NSAIDs and most prophylactic medications such as antidepressants and epilepsy drugs.

The concept of acute medication “overuse” may be unhelpful and stigmatizing, as it suggests frequent attacks are the patient’s fault rather than a disease manifestation. Optimizing acute treatments may naturally reduce the need for frequent medication use as attacks improve.

 

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A new report suggests that CGRP-blocking drugs (CGRP-A) are safe in pregnancy.

In the latest study, Swiss doctors examined the World Health Organization’s pharmacovigilance database and looked at reporting differences between CGRP drugs and triptans.

Triptans (drugs like sumatriptan or Imitrex and six others) were introduced over 30 years ago.  We know from pregnancy registries, retrospective, and prospective observational studies that triptans are safe in pregnancy.

The WHO database had 467 safety reports of exposure to CGRP-A in pregnancy. Of these, 386 were reports of exposure to CGRP monoclonal antibodies (mAbs), 76 to gepants, and 5 to both. The authors found “…no signals of increased reporting with CGRP-A compared to triptans in relation to pregnancy”.

CGRP drugs represent a major breakthrough in treating migraine headaches. A large proportion of migraine sufferers are women of childbearing age. We always have to consider the effect of a drug on the developing fetus. Erenumab (Aimovig), the first drug in this category was introduced almost six years ago. This is a relatively short period to assess the safety of a drug in pregnant women and the current report is not a definitive proof of safety.

There might be a difference in safety between oral CGRP antagonists (gepants), which are small molecules and injectable mAbs, which are large molecules. Gepants have the advantage of being completely washed out of the body within a few days of stopping them.  Monoclonal antibodies are injected every one or three months and can take a few months to completely leave the body. However, mAbs, being larger, cannot cross the placenta in the first trimester. So if a mAb is stopped at the beginning of pregnancy the exposure to the fetus will be small.

The gepants include ubrogepant (Ubrelvy), rimegepant (Nurtec), atogepant (Qulipta), and a nasal spray, zavegepant (Zavzpret). The monoclonal antibodies are erenumab, fremanezumab (Ajovy), galcanezumab (Emgality), and eptinezumab (Vyepti).

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A new study by Harvard researchers suggests that there is no connection between caffeine consumption and migraine headaches. I am not convinced. This study was small and had only 12 out of 97 participants consume 3-4 cups a day, while 65 consumed 1-2 cups and 20 consumed no caffeine. Statistics based on such small numbers are unreliable.

Most headache sufferers who drink large amounts of caffeine develop a caffeine-withdrawal headache when they don’t get their usual dose of caffeine on time.  My most dramatic case was that of a man who drank about 10 cups of coffee a day. He also set an alarm for 3 AM to have a cup of coffee. If he skipped that 3 AM cup, he would wake up with a debilitating migraine.

A double-blind caffeine withdrawal study published in the New England Journal of Medicine. It showed that 52% of people consuming an average of 2.5 cups of coffee developed a moderate or severe headache when caffeine was stopped.

Caffeine can play positive role in the treatment of migraine and tension-type headaches. It is considered to be an adjuvant analgesic and is included in over-the-counter and prescription drugs along with pain medications. It enhances pain relief produced by acetaminophen, aspirin, and other pain drugs.

The problem arises from excessive intake of caffeine. Two cups of coffee at breakfast, a cup of caffeinated soda at lunch, and a couple of Excedrin do not appear excessive until you consider the total amount of caffeine in these products. If you are prone to headaches, this amount may be sufficient to cause a headache, typically upon awakening in the morning.

 

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