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.
Headaches
I will be speaking on nutritional supplements for migraines and an update on triptans on April 20, 2024.
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.
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.
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).
Read MoreA 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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Because of my research and publications on magnesium, I was contacted by Nutrisense. This company helps people without diabetes improve their diet and “metabolic health”. They are interested in educating people about the role of magnesium, a very underappreciated mineral. The company offered me a free 2-week trial of their continuous glucose monitor (CGM). I have a healthy diet and normal weight so I was not sure that I could get any useful information. But I thought that some of my patients could benefit and wanted to see what they would experience.
CGM did provide some interesting observations. After exercise, I gulped down 12 oz of unsweetened coconut water. My glucose went up to 150, the upper limit of what is considered normal. I ate a golden delicious apple for a snack one afternoon. Healthy, isn’t it? My glucose level shot up to 165. The next day, I went to a birthday party for a 3-year-old and ate two slices of pizza, without toppings. The glucose level went up to 164. Another night, I had some sushi. The level was 169 (sushi rice is always cooked with sugar). Then, after dinner out with my family, we decided to have ice cream. I had two scoops with the good excuse of wanting to see how high my glucose would go. Surprisingly, it went up only to 151.
It is well known that eating protein and fat first will slow down the absorption of carbohydrates. This is why an apple, eaten between meals gave me a higher spike in sugar than two scoops of ice cream I ate after dinner. Any liquid form of sugar gets absorbed fast. So, you may want to avoid sweet drinks, including fruit juices. I found that getting feedback from the CGM helped modify my eating habits, mostly for the better. I may be less inclined to avoid desserts after dinner. However, additional calories do make me gain weight, so I will try to control myself.
A few caveats. Whenever I slept on the side where my CGM was attached, the glucose level appeared to drop to dangerous levels. This incorrect reading happens when compression restricts blood flow to the monitor. Occasionally, when exercising, I felt a poke from the needle of the CGM. And, after two weeks, my skin became a bit irritated by the sticky bandage that covered the CGM.
I may recommend CGM to my patients who get migraines when they are hungry and to those who are looking for additional help in losing weight. In addition to getting direct feedback about the impact of food on their sugar levels and those levels on their migraines, some patients may benefit from a consultation with a dietitian. Nutrisense can connect you with a dietitian.
My reactions to various foods were normal. Hunger is not one of my migraine triggers. However, many people with migraines have reactive hypoglycemia – an exaggerated response to carbohydrates. This means that when the blood glucose level spikes after a carbohydrate-rich meal, too much insulin is produced, and the glucose level drops below normal. This can be a migraine trigger. Even if migraine is not triggered, this can also make you sluggish and less productive. Skipping meals is also a known migraine trigger and the mechanism is similar – your blood glucose drops too low. There is also a strong correlation between weight and migraines – the heavier you are the more migraines you get. Women with polycystic ovarian syndrome (PCOS) are at a higher risk of having insulin resistance and developing diabetes.
The ideal diet is low in carbohydrates and high in protein. Three or four meals a day is the frequency that works best for most people. In general, the last meal should be at least two hours before bedtime. But there are exceptions. For some, having a snack in the evening prevents morning or middle-of-the-night migraine.
Read MoreI am once again honored to participate in the annual meeting of the Headache Cooperative of the Northeast to be held March 7-9 at the Stamford Marriott Hotel and Spa in Stamford, CT.
You will get a chance to learn about the latest scientific breakthroughs from Rami Burstein, president of the International Headache Society. You will also hear from other prominent figures in the field, renowned for their pioneering work and extensive contributions over several decades – Drs. Steven Baskin, Elizabeth Loder, Thomas Ward, Morris Levin, Richard Lipton, Steven Silberstein, Allan Purdy, Alan Rapaport, Paul Rizzoli, Sait Ashina, and others.
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We use a neuronavigation system from Soterix (on the left) for precise targeting of transcranial magnetic stimulation (TMS). And we use the most advanced TMS machine from MagVenture (on the right) to treat chronic pain, migraines, fibromyalgia, and other neurological conditions.
Medication overuse or rebound headaches can occur as the result of excessive intake of caffeine, opioid analgesics, and short-acting barbiturate drug, butalbital (contained in Fioricet, Esgic and similar drugs). These three substances not only worsen migraine headaches, they are also addictive. Two of my patients with medication overuse headaches were able to stop the offending drugs with the help of repetitive transcranial magnetic stimulation (rTMS).
One patient, a 51-year-old man, had his migraines under control with Botox and infusions of eptinezumab (Vyepti) until he sustained a head injury with a skull fracture. His migraines worsened and he became disabled. A variety of therapies failed to reduce his pain. His pain was partially relieved by 60 mg of oxycodone a day, although he still was unable to work. After six weekly sessions of rTMS he was able to start reducing his oxycodone intake and after eight, he completely stopped it. He was able to return to work with the help of injections of fremanezumab (Ajovy).
Another patient, a 50-year-old woman, had been taking butalbital with caffeine and acetaminophen (Fioricet) for 20 years. The number of pills increased over time and for the previous several years, she had been taking 10 to 12 tablets every day. She was also receiving Botox injections, infusions of eptinezumab, and taking rizatriptan (Maxalt), 10 mg three times a day as well as 60 mg of nortriptyline, 12 mg of tizanidine nightly and atogepant, 60 mg. She had tried a wide variety of other treatments but was unable to reduce her Fioricet intake. Despite her persistent migraines, she was able to take care of her family. After three weekly sessions of rTMS she reduced her Fioricet intake to 3-4 a day, by the third month she was taking one a day, and after 6 months she was completely off it. She was also able to stop atogepant and tizanidine and reduced her nortriptyline to 25 mg.
In addition to helping relieve pain and migraines, rTMS has shown promise in the treatment of addiction, particularly in addressing withdrawal symptoms, depression, and cravings. While the use of rTMS for addiction is still relatively recent and not yet FDA-approved, some studies have demonstrated positive outcomes. For instance, a double-blind study showed that individuals receiving rTMS therapy for cocaine addiction had a higher rate of abstinence compared to those who received standard treatment. rTMS for addiction is still considered experimental, and more research is needed to fully understand its long-term effects and optimal treatment parameters.
Read MoreNeurologists 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.
Read MoreProton Pump Inhibitors (PPIs) are a class of medications commonly used to treat conditions such as acid reflux, ulcers, and heartburn. They include omeprazole (Prilosec, Zegerid), esomeprazole (Nexium), lansoprazole (Prevacid), rabeprazole (AcipHex), Dexlansoprazole (Dexilant), and pantoprazole (Protonix). Several of these are available without a prescription.
While PPIs are generally considered safe and effective, several studies have suggested a potential association between PPI use and several medical and neurological problems. These include osteoporosis, kidney problems, impaired hearing, vision, memory, and an increased risk of conditions such as migraines, dementia, peripheral neuropathies, and seizures. The evidence is circumstantial and not definitive. However, considering the large number of studies and a large number of conditions, PPIs are probably not safe for long-term use.
In the case of migraines, one study found that past and current use of PPI increased the odds of migraine by 2.56-fold and 4.66-fold, respectively. The exact reason for this link is still a mystery, but researchers are exploring several possibilities:
Nutrient deficiencies: PPIs can interfere with the absorption of important nutrients like vitamin B12, other B vitamins, and magnesium, which can contribute to headaches.
Gut microbiome changes: PPIs can alter the gut microbiome, which may indirectly impact brain function and migraine susceptibility.
Inflammation: Some studies suggest PPIs might trigger low-grade inflammation, a potential factor in migraine development.
This post was prompted by a recent study showing an association between PPI intake and the risk of dementia. Those who used PPIs for a cumulative four and a half years or longer had a 33% higher risk of developing dementia.
Stopping a PPI can cause severe rebound acidity. This is why people get stuck taking them for years. The way to try is by replacing the PPI with an H2 blocker such as famotidine (Pepcid, Zantac 360) along with an antacid such as Rolaids (it’s better than Tums because it contains not only calcium but also magnesium) or Gaviscon. After a few weeks, people can often stop famotidine and after another few weeks, stop the antacid. Famotidine does not cause problems associated with PPIs.
If you cannot stop or have a condition that requires long-term intake of a PPI (e.g. Barrett’s esophagitis), make sure to take a variety of vitamins and minerals. However, the lack of acidity can prevent the absorption of supplements. We usually do a blood test to check vitamin B12, RBC magnesium, vitamin D, and others. Some of our patients come in for monthly infusions of magnesium and other nutrients they are deficient in.
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