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Migraine

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

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

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

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

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

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

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

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

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

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Magnetic stimulation with a single pulse has been shown to be effective in aborting a migraine attack with the eNeura Spring TMS device.
Repetitive magnetic stimulation (rTMS) of the brain has been shown to relieve depression. A pilot study just published in the journal Brain Stimulation examined the effectiveness of repetitive magnetic brain stimulation for the prevention of migraine attacks.

German and Moldovan researchers conducted a double-blind, randomized controlled study in patients with episodic migraine. They compared real and sham stimulation in 60 patients. Participants received six treatment sessions over two weeks. The primary outcome measure was the number of patients whose migraine days dropped by 50% or more. The frequency and intensity of migraine attacks over a 12-week period were also assessed.

Real rTMS produced at least a 50% reduction in migraine days in 42%. This number was 26% in the sham group. The mean migraine days per month decreased from 7.6 to 4.3 days in the real rTMS group and from 6.2 to 4.3 days in the sham rTMS group. The reduction in migraine attack frequency was also higher in the real rTMS compared to the sham group. No serious adverse events were observed.

There are a couple of practical issues with this treatment approach. The rTMS equipment is already being used for depression, which in theory should make it easy to adapt for migraines. However, this treatment is time-consuming and expensive and is not likely to be covered by insurance. Another problem, which we also encountered in our study of transcranial direct current stimulation, is that there are many variables to consider. Placement of electrodes, the strength of stimulation, frequency, and duration of treatments are some of these variables.

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Ketamine was approved by the FDA in 1970 and was originally used for the induction of anesthesia. It has been shown to relieve depression and is also widely used to treat pain. For depression, it is approved by the FDA in a nasal spray form. For severe pain, it is often given intravenously. Oral ketamine is probably the least effective.

In a recent study, Australian researchers compared the pain-relieving effect of oral and sublingual ketamine in 16 patients. The study was double-blind. Sublingual administration of ketamine resulted in a faster onset of pain relief – 7 minutes with sublingual and 13 with oral. Side effects were also more common with the sublingual route. In all other measures, sublingual and oral administration produced similar pain-relieving effects.

Oral and sublingual ketamine are not available at regular pharmacies. It is, however, easily made up by compounding pharmacies. The sublingual ketamine is available as a lozenge which is also called troche. I usually prescribe ketamine infusions or troches only after a wide variety of other treatments do not provide relief.

Ketamine is a controlled drug with a potential for misuse. It can also cause psychiatric side effects such as hallucinations, disinhibition, delusional thinking, and depression.

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

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The placebo effect is a bane of clinical trials. It is, however, a great tool in clinical practice. It is unethical to prescribe an actual placebo but there is no reason not to try to enhance the placebo effect when prescribing any treatment, pharmacological or non-drug.

A new and unique study that was just published in Pain, a journal of the International Association for the Study of Pain, suggests that looking at others who respond to treatment makes people more likely to respond to that treatment as well.

German researchers decided to study what is called social observational learning (SoL). This was a double-blinded randomized controlled clinical trial in 44 patients with chronic low-back pain (CLBP). They compared the effects of observing positive treatment outcomes in a sham or pretend patient versus hearing the same sham patient report neutral effects. In the SoL group, the sham patient told study patients about his improved pain due to amitriptyline and he also demonstrated his improved mobility by bending forwards and sideways. The same sham patient told the control group only that he was taking amitriptyline. The researchers collected data before and after the intervention and two weeks later. After the intervention, pain decreased in both groups with no difference between groups. The SoL group, however, showed a significantly larger decrease in perceived disability.

The authors concluded that “The CLBP patients’ direct observation of positive treatment outcomes in the sham patient appears to have enhanced the treatment effects, while indirect verbal reports of reduced pain did not.”

These findings are not surprising. I often have patients ask for a particular treatment because their friend or relative had a very good response to it. If it is a reasonable treatment for a particular patient, I usually oblige, hoping for an enhanced placebo effect.

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I am honored to participate in a symposium on headache management,
“THE CHALLENGE OF MIGRAINE AND CLUSTER HEADACHES”. The title of my presentation is The challenge of migraine: new perspectives in refractory cases

This interactive neurological conference will be held in-person on Thursday, November 4, 2021 at the Zurich Marriott Hotel, Zurich, Switzerland

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To gain FDA approval a drug has to be shown to be better than a placebo. The placebo effect is a well-established psychological contributor to the efficacy of most treatments.

A group of Italian researchers just published an interesting study looking at other psychological factors that might influence the response to treatment.

They evaluated chronic migraine patients who were treated with erenumab (Aimovig). Erenumab is a monoclonal antibody that targets CGRP, a neurotransmitter involved in the development of migraine attacks.

Monthly erenumab injections were given for one year to 75 patients with chronic migraine who had already failed at least three other oral preventive drugs. A full psychological evaluation assessed personality disturbances, mood and anxiety disorders, as well as childhood traumas, and ongoing stressors.

After 12 months of treatment, 53 patients had at least a 50% drop in the number of headache days per month. The other 22 did not. When compared to responders, non-responders were more likely to have personality disorders with anxious-fearful, avoidant, dependent, and obsessive-compulsive features. Non-responders were also more likely to suffer anxiety disorders and had a higher number of current major stressors.

A very practical application of these findings is that doctors need to address anxiety when treating migraine and chronic pain patients. I’ve seen a number of patients whose migraines improved with an SSRI antidepressant such as fluoxetine (Prozac) or escitalopram (Lexapro). SSRIs do not possess pain-reliving properties. However, they are good at relieving anxiety and so can indirectly improve migraines. Most of the time, I prescribe SNRIs such as duloxetine (Cymbalta) or a tricyclic antidepressant such as nortriptyline (Pamelor) because they relieve anxiety and can have a direct pain-relieving effect.

The old dogma in psychology was that you cannot change your personality. We now know that such change is possible. Different types of cognitive-behavioral therapy (CBT) can be very helpful. Swedish researchers showed that even a brief internet-based CBT can produce long-term changes in personality traits.

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Atogepant (Qulipta) is a new migraine drug that was just approved by the FDA for the preventive treatment of migraines. It is the third drug in the family of gepants. Gepants block the CGRP receptor. CGRP is a chemical released during a migraine attack. In the past three years, the FDA approved four injectable preventive migraine drugs that also block CGRP. Gepants are taken by mouth.

The dose of atogepant is 10 mg, 30 mg or 60 mg taken daily, once a day. The primary efficacy endpoint in clinical trials was the change from baseline in mean monthly migraine days over the 12-week treatment period. There was a drop of 3.7, 3.9, and 4.2 in the number of mean monthly migraine days in the 10 mg, 30 mg, and 60 mg doses, respectively.

Side effects – assessed in almost 2,000 patients – were infrequent and mild. Nausea occurred in 5%, 6%, and 9% on 10 mg, 30 mg, and 60 mg respectively, constipation in 6% on all three doses, and fatigue or somnolence in 4%, 4%, and 6%.

Ubrogepant and rimegepant, two other gepants, were first approved to be taken as needed, whenever a migraine strikes. Rimegepant recently was also approved for the prevention of migraines. Even though gepants are very similar they often differ in how they work in an individual patient. Some of my patients find that ubrogepant works much better than rimegepant while for others the opposite is true. I am certain that some patients will find a big difference in the way rimegepant and atogepant work for them. This is why it is useful to have a few drugs in every therapeutic category.

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Many migraine sufferers report that their migraines are brought on by the weather. High humidity, high temperatures, and changes in barometric pressure are the most commonly reported triggers. I’ve seen some patients for whom changes in the weather is the only trigger. Research studies looking at this connection, however, have been contradictory.

A very large study just published in Pain, the journal of the International Association for the Study of Pain examined a possible connection between the weather and pain tolerance.

The data from 18,000 Norwegians aged 40 years or older from the general population were examined. All of them underwent pressure pain tolerance (PPT) test using a blood pressure cuff and cold pain tolerance (CPT), tested by immersing the dominant hand in cold water.

The results showed a clear seasonal variation in CPT. Cold pain tolerance was worse during the warmer times of the year compared with January. There was no seasonal variation in PPT.

The authors also found that temperature and barometric pressure have “a causal and dynamic effect on pain tolerance, which supports the common belief that weather affects pain.”

There is not much you can do about the weather except for moving to a place with an unchanging and mild climate. Some of my patients with barometric pressure-induced headaches do respond to acetazolamide (Diamox). This is a diuretic that prevents mountain sickness in climbers. Patients do not need to constantly check the weather forecast. For more information on acetazolamide, see my previous blog post.

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Trudhesa is a new formulation of dihydroergotamine (DHE) nasal spray just approved by the FDA. It appears to be more effective than the original DHE nasal spray (Migranal) that was introduced in 1997.

Ergotamine, the first migraine-specific drug was developed in 1926. It is still available in tablet form but is not widely used because it causes nausea, constriction of blood vessels, and other side effects. DHE, approved in 1946, was the first synthetic migraine drug. It was derived from ergotamine in an attempt to reduce side effects. DHE is not effective when taken by mouth and was originally approved for intravenous use. It is still being used now – 75 years later – intravenously, intramuscularly, and subcutaneously. DHE injection is a very effective medicine, often used when no other migraine drug provides relief. It does cause nausea and vomiting in a significant number of patients. This is why it is often given along with an anti-nausea drug such as ondansetron (Zofran), prochlorperazine (Compazine), or metoclopramide (Reglan).

The original DHE nasal spray has been a relative disappointment. It is not very effective, although there are some patients for whom it works well. Despite being on the market for over 20 years, it is still very expensive – $100 a dose. The manufacturer of Trudhesa, which is a better product than Migranal, is promising to make their product more affordable. Nasal delivery of DHE causes less nausea than an injection.

Trudhesa is more effective despite delivering a smaller dose of DHE than Migranal. This is because Trudhesa is delivered as a fine mist into the upper reaches of the nasal cavity. It will become available in about two months. I will prescribe it to patients for whom oral medications are ineffective.

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The placebo effect is a bane of clinical trials. A drug is considered ineffective if it is only as good as a placebo. And placebo can be quite good. Intriguingly, the placebo effect in clinical trials has been getting stronger over the past few decades. Lately, placebo has been receiving a lot of attention from researchers.

A rigorous study just published in the journal Pain looked at the effect of a placebo when patients were clearly told that they are taking a placebo. These patients were compared to those who were given a placebo in a double-blind study of peppermint oil capsules for irritable bowel syndrome (IBS). These two different types of placebo were compared to a control group of patients who were not given any pills.

Participants treated with an open-label placebo and a double-blind placebo reported similar and clinically meaningful improvements in IBS symptoms. These improvements were significantly greater than in those who were not given any pills. The results were statistically significant for the primary outcome measure (IBS Symptom Severity Scale) as well as for mean global improvement scores.

Twice as many patients in the double-blind placebo group had side effects (mostly gastrointestinal, such as heartburn) than those in the open-label placebo. It is probably because the first group was told about the possible side effects of peppermint oil.

The authors concluded that an open-label placebo “could play a role in the management of patients with refractory IBS”.

Just like migraines, IBS involves central sensitization and hypersensitivity of the nervous system. And just like with migraines, placebo response in clinical trials of IBS tend to be high. This is not to suggest that these conditions are psychological. Especially with migraines, the biological basis is well documented. Psychological factors, however, cannot be ignored. About 40% of patients with chronic pain, including migraines, have a history of emotional, physical, or sexual abuse. Post-traumatic stress disorder of other types also causes hypersensitivity of the central nervous system. Psychological factors can even be the cause of such potentially deadly conditions as broken heart syndrome (Takotsubo cardiomyopathy). It is likely that the placebo effect is stronger in conditions where psychological factors are more pronounced.

It is considered unethical to prescribe a placebo to patients without telling them that they are getting a placebo. This latest study suggests that some patients may improve even if they know that they are taking a placebo.

I do prescribe herbal supplements such as feverfew and boswellia and on a rare occasion, a homeopathic remedy, all of which lack rigorous proof of their efficacy. For that matter, many drugs we prescribe for migraines lack such definitive proof. I would suggest that we should first prescribe less harmful unproven remedies rather than unproven prescription drugs.

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It is gratifying to know that my colleagues consider my new book, The End of Migraines: 150 Ways to Stop Your Pain, to be useful for patients with migraines as well as doctors who treat them.

Dr. Uwe Reuter of Charité Universitätsmedizin Berlin, Germany has published a review in the latest issue of the journal of the International Headache Society, Cephalalgia. He concludes his review, “I am happy to encourage everybody who is interested in migraine to read this e-book.”

Dr. Allan Purdy published a review of my book in May in the journal of the American Headache Society, Headache. His review was much longer and so was the conclusion:
“I would recommend this book to anyone who has migraine or cares for people with migraine and wants a broad and sometimes detailed overview of the treatments. Available in the e-book format, it represents a lot of work for one person, but his passion, occasional humor, and historical perspectives are evident in this work. You don’t have to agree or accept everything the author says to enjoy and benefit from this “book,” and I know he would want people to be critical and skeptical where warranted. However, you will find more than you would usually need to know from this banquet of 150 ways to help your migraines! Enjoy, I did very much. Read it through once and save as reference.”

If you do read this book, please write a short review on Amazon.com.

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