Thinking about COVID-19 almost gives me a migraine, or at least a heavy and achy sensation in my noggin – perhaps not an actual migraine, thankfully, but threatening and unpleasant all the same.   Happily, thinking about migraines will not give me COVID-19.   But migraines are by no means a topic of no consequence, even when COVID-19 is on our collective minds.   Migraine has been characterized as the most painful non-fatal ailment.   And, make no mistake, migraine really is an ailment – an illness or disease – and certainly much more than a casual headache. 

The bit of news that steers me to thinking about migraines once again came from the results of the OVERCOME study, which looked at a nationally representative sample of 21,143 persons who had a diagnosis of either chronic or episodic migraine.   (Buse D. Neurology 4/14/20:15 Suppl)

This was a study in what is described as “acute treatment optimization,” which supposedly contributes to reduced disability and improved health-related quality of life.   What was surprising and disturbing about the OVERCOME study is the finding that a large percentage of persons with migraine, whether chronic or episodic, simply did not receive treatment – either acute treatment, meant to help to resolve a migraine headache in progress, or prophylactic treatment, meant to help prevent recurring migraine episodes.   These individuals were not just plain folks who had occasional bad headaches that they figured were probably migraines.   Most of them had received a migraine diagnosis from a health professional, and nearly all had fulfilled the diagnostic criteria of the American Migraine Study.   More than half had at least a mild migraine disability, meaning that migraine episodes had the effect of preventing them from living their normal daily lives – missing work, or keeping to their beds in a darkened room.   About a quarter had such migraine headaches at least four times per month.       

Rejection of medical treatment of any kind can be based on many different factors, some more rational than others.   For example, a person who experiences an occasional migraine might rationally decide that he/she prefers to tough it out than to take a drug that is supposed to prevent the migraine, but is linked to side effects of consequence.   And that person might also be reluctant to take a drug for the acute treatment of migraine if that drug is known to be associated with rebound – that is, after the initial palliative effect of the drug, the migraine returns.   However, the OVERCOME study found that only about 20% of the individuals who experienced 15 or more migraine headaches per month took preventive drugs.   The percentage of those severely affected individuals who took acute treatment drugs was higher – 35%.   But that still meant that about two-thirds of persons who experience migraine headaches very frequently – about every other day – do not take drugs to manage their symptoms.   

Why might this be?   What it comes down to, in the opinion of Doc Gumshoe, is that migraine drugs, whether for acute or prophylactic treatment, do not have a reputation for a high level of efficacy.   

Coming up with drugs for the treatment of migraines is a complex task, made more complex by several factors.   One is that a migraine is much, much more than a bad headache.   Migraines are almost always accompanied by a range of non-headache symptoms that complicate the treatment options.   About 80% of the time migraines come with bad GI symptoms, including nausea and vomiting, which makes treatment with usual analgesics much less effective.

Another factor is that the precise etiology of migraines is not yet clearly understood.   As you know, in most cases drug treatment takes careful aim at the causes of an illness or condition.   If the condition is an infection, one directs the bullet at the pathogen.   If it is hypertension, the treatment aims at the mechanisms that raise blood pressure, such as constriction of the arteries.   But in the case of migraines, the target is not sharply outlined.

Let’s step back and take a look at migraine and what is known (or speculated) about its causes.   A headache is not considered to be a migraine unless it is accompanied by other clinical symptoms, the most usual of which is nausea, sometimes with vomiting.   Migraineurs (which is what people afflicted with migraines are called) are also extremely sensitive to light and sound, frequently taking refuge in dark, quiet rooms when they feel a migraine coming on.   In some cases, odors which are not usually thought to be unpleasant are intolerable to the migraineur.   And, in addition to the acute head pain, they may experience blurry vision, stuffy nostrils, diarrhea, stomach cramps, pallor, flushing, or localized swelling of the face, hot or cold sensations, sweating, stiff neck, tenderness of the scalp, and a range of mental symptoms including anxiety, depression, irritability, and impairment of concentration.

Visual auras are also experienced by some migraineurs.   These can be arcs of flashing lights in a zigzag or herringbone pattern passing across the visual field and growing in size.

Many migraineurs can feel the migraine coming on.   These are known as “prodromal symptoms,” and sometimes, but not always, migraineurs can head off the migraine by taking action.   Sometimes simple activities can prevent the onset of the full-fledged migraine – vigorous exercise, a hot or cold shower, sex (yes, sex!), or a bite of food.   

How common are migraines?

In the US, somewhere around 10% of the population experience at least one migraine headache per year.   That is about the same as the global prevalence of migraines.   Migraines affect women more than men – about 18% of women have migraines, compared with about 6% of men.   Migraines account for about two-thirds of severe headaches in women and just over 40% in men.

Migraine incidence starts earlier in boys than in girls – about age 5 for boys and 12 to 13 for girls.   However, prevalence is greater in females than males – about 2.5 to 1 at puberty, increasing to 3.5 to 1 after age 30.   Migraines tend to decrease both in frequency and severity after age 40. 

In the US, the cost of migraines resulting from loss of work time is calculated at more than $13 billion per year.   Male migraineurs typically require about 4 days of bed-rest per year, and females need almost 6 bed-rest days per year.

What do we know about the cause of migraines? 

The essential root cause of migraines is still somewhat mysterious.   The last time I wrote about migraines I quoted two sentences from two recent papers about the pathophysiology of migraine.   The first is the very last line from a paper entitled “Migraine: Multiple Processes, Complex Pathophysiology.”   (Burstein R. J Neuroscience 2015;3 5;6619-6629)   

 “Given the enormous burden to society, there is an urgent imperative to focus on better understanding the neurobiology of the disease to enable the discovery of novel treatment approaches.”

What the authors of that paper are saying is that, despite a great deal of meticulous research into the possible causes of this disorder, they are quite far from having it nailed down. 

The second sentence is the first line from a paper by Peter J. Goadsby, who recently chaired the meeting of the American Headache Society.   (Goadsby PJ. Ann Indian Acad Neurol 2012;15(Supp1)S1-S22)   

“Migraine is likely to be a brain disorder involving altered regulation and control of afferents, with a particular focus on the cranium.”

I call your attention to the word “likely.”   (“Afferent” in that sentence refers to signals travelling to any of various brain centers rather than away from those centers.)   Goadsby is saying that the cause of migraine is more likely to be a brain disorder than a disorder of the vascular system, which was the explanation that had held sway for quite a number of years.   That previous explanation was that the migraine headache was caused by the dilation of blood vessels around the periphery of the brain.   The idea was that these dilated blood vessels would press on the sensory nerve endings, which would naturally result in a headache.   This theory, the “vascular hypothesis” is supported by the greater prevalence of migraines in women; estrogen makes blood vessels more flexible, which makes them more likely to dilate and press on nerve endings.

But the vascular hypothesis fails to account for the observation that migraines are almost always on one side of the head only; why would the vasodilation phenomenon be unilateral?   Also, brain imaging studies have shown that during the headache phase of the migraine, blood flow is not increased, which would be the case if the cause of the headache were vasodilation.       

An alternative theory, which has more recently gained currency, is the sterile inflammatory response hypothesis.   (A sterile inflammatory response, as the name suggests, is an inflammatory response to a non-infectious trigger.)    This suggests that the migraine symptoms result from the release of plasma, which can press on the trigeminal nerve fibers, resulting in pain.    

Several substances have been identified as possibly or likely to be involved in the pathway that leads to the characteristic headache pain.   These include calcitonin gene-related peptide (CGRP) and another peptide labeled substance P, which conveys pain information.   Research into forms of treatment that block these neurotransmitters has demonstrated some effectiveness in preventing migraines. .

Another chain of reactions that is linked to migraines involves glutamate release.   A mutation which is common in about half of persons who are migraine sufferers involves the calcium channel gene.   The calcium channel transports calcium ions from the plasma into cells throughout the body.   This particular mutation results in increased release of glutamate.   Perhaps not coincidentally, a similar mutation, also resulting in higher circulating levels of glutamate, is linked with epilepsy and seizures.   This may have some bearing on the widely reported heightened sensitivity to monosodium glutamate (MSG) reported by some individuals who experience migraines. 

The most successful theory, from a purely pragmatic perspective, is that migraine is a syndrome characterized by low levels of serotonin in the plasma.   Serotonin (5-hydroxytryptamine, or 5-HT) has a number of physiologic effects, including the ability to suppress pain and to contribute to normal sleep.   The evidence is as follows: first, during the headache phase of a migraine episode, the main metabolite of 5-HT is found in increased amounts in the urine (meaning that it is being broken down more quickly); second, during the onset of the migraine attack, 5-HT levels fall by as much as 40%; third, agents that deplete amines including 5-HT can trigger a migraine attack; and, fourth, intravenous 5-HT can abort migraine attacks.   However, we need to note, intravenous 5-HT has a number of adverse effects, such as rapid vasoconstriction and increases in blood pressure, which make it unacceptable for clinical use.

Serotonin acts through a number of receptors, classified as 5-HT₁ through 5-HT_7.   The 5-HT₁ subclass includes those most likely to be involved in pathophysiology of migraine, especially 5-HT_1B and 5-HT_1D.   Most of the current generation of migraine medications  –  i.e., the triptans, which we’ll say a bit more about later – are activators of those serotonin receptors.   They are both potent constrictors of blood vessels in the brain, and, perhaps more important, inhibitors of the sterile inflammatory response.

What all this comes down to, however, is that the root cause or causes of migraines have not been precisely identified.   It’s clear that something is impacting the nociceptors (the nerves that detect any possible damage and transmit a warning signal in the form of pain) in the brains of migraineurs, whether it’s the dilation of the blood vessels in their immediate proximity, or an inflammatory reaction in the brain tissue triggered by an ionic reaction, or a deficiency in circulating serotonin, or an excess of glutamate, or a number of other reactions.   These possible pathologies continue to be investigated, and more effective treatment modalities for migraine will – we hope! – emerge.   

So, what medications have some migraineurs (at least) found to be helpful?

For a start, many of the over-the-counter analgesics that are specifically marketed as anti-migraine drugs are only marginally effective.   In a recent survey of migraineurs, only 17% reported that they got “a lot” of relief from these drugs.   The efficacy of prescription analgesics sometimes prescribed for migraines was no better.   A problem with the use of analgesics for migraine relief is that one of the effects of the migraine is gastric stasis.   That means that the pain killer doesn’t get absorbed, and indeed may aggravate the nausea that migraineurs usually experience.   So, while the usual remedy for non-migraine headaches is an analgesic, this mostly does not work for migraines.   The use of drugs usually used to treat depression or anxiety has been suggested as a potential way to provide relief of the migraine headache.   However, these seem to work even less well than analgesics – only about 4% of migraineurs got “a lot” of relief from these psychoactive drugs.

Some older antidepressants, such as the tricyclic amitryptaline, as well as the anti-seizure drug topiramate are used chronically by some migraineurs.   A new formulation of topiramate, Qudexy XR (Upsher-Smith Laboratories) was recently approved by the FDA for prevention of migraine in adults and adolescents over the age of 12.   The newly approved drug is an extended-release formulation which, it is hoped, will also improve adherence to migraine prophylaxis.   As you may have noticed earlier in this piece, only about 20% of persons who experience frequent migraines stick with prophylaxis, so any improvement in adherence should be seen as a good thing.   I’ll say a bit more about migraine prophylaxis later in this piece.                                                                                                         

A definite drawback with these drugs is that they cannot be taken in response to a specific migraine episode.   Instead, in order for them to be at all helpful, some of these drugs need to be taken every day, although some of the newer prophylactic drugs can be taken monthly or even quarterly..   However, the risk of adverse effects increases with chronic use of any drug, and one would have to weigh these risks extremely carefully before taking a drug to prevent migraines that only occur sporadically.

The first drugs specifically developed to treat migraines drugs were the triptans, which are agonists (activators) of certain serotonin receptors, designated 5-HT_1B/1D.   The first of these was sumatriptan (Imitrex, from Glaxo SmithKline), initially marketed as a subcutaneous injection and later as an oral medication.   At least six other triptans have followed sumatriptan, and sumatriptan is now available as an oral medication, a nasal spray and also in combination with naproxen.   

Most triptans usually provide reasonably prompt headache relief – i.e., within less than 2 hours.   However, there are significant drawbacks to triptan use.   One is that many migraineurs experience recurrence of headaches after initial relief.   In some studies, 40% to 70% of migraineurs reported rebound headaches, and repeated dosing with triptans is usually not recommended.   Thus, rather than taking the triptan, some migraineurs prefer to seek relief without any specific drug treatment, using their own strategies – bed-rest in a darkened room, ice-packs, warm compresses, scalp massage, sleep.

Another significant drawback is that, since a principal mechanism of action of the triptans is vasoconstriction, there is some associated cardiac risk, and migraineurs who have heart disease risk factors are not recommended to take triptans.

The differences between the seven triptans are fairly minor.   Here’s a quick summary of the chief differences:

• Imitrex (sumatriptan, GSK) in a subcutaneous formulation has the fastest onset of action, about 10 minutes.    

• Zomig (zolmitriptan, Impax) is available in a nasal formulation, whose onset of action is just a bit slower than that of Imitrex.   

• Amerge (naratriptan, GSK) onset of action may be as long as 3 hours – the longest of any triptan.   

• Axert (almotriptan, Janssen), Relpax (eletriptan, Pfizer), Frova (frovatriptan, Endo), Maxalt (rizatriptan, Merck), as well as the tablet formulations of Imitrex and Zomig, have onsets of action ranging from 30 minutes to perhaps 2 hours.

• Frova has the longest duration of action, up to 6 hours. Most of the triptans have a fairly short duration of action, in the neighborhood of 2 hours.

• Probably the most effective triptans are Imitrex and Relpax..

• Axert and Maxalt are approved for pediatric use – Axert in children age 12 or older, and Maxalt in children age 6 or older.   The nasal formulation of Zomig  is also approved for children age 6 or older.

• Patients taking the short-acting triptans often take a repeat dose to get them through their migraine episode, even though this is generally not recommended.    

• The adverse effects that clinicians will be on the alert for in their patients taking triptans are cardiovascular.   The subcutaneous Imitrex formulation is associated with the greatest cardiac risk, while Axert appears to have the lowest cardiac risk.  

• Amerge (naratriptan) has the lowest incidence of side effects, followed by Axert (almotriptan).

Migraineurs by no means need to stick with one triptan.   If he or she (she, usually) feels the headache coming on quickly, the best option might be the subcutaneous Imitrex or perhaps the nasal Imitrex or Zomig.   Those same options might be optimal for the person who has to cope with nausea and might not be able to manage the oral triptan formulations.   On the other hand, if the migraineur is in the grip of an extended bout of prodromal symptoms and anticipates a long-lasting headache, the optimal choice might be Frova.

The differences between those seven triptans suggests that in the event that a migraineur does not get a satisfactory response to any individual triptan, the patient and clinician should keep trying the alternatives.   The overall response to subcutaneous Imitrex, one of the most effective triptans, is about 70%.   But there is evidence that in the 30% of patients who do not respond to Imitrex, up to 80% will respond to another triptan.   So, adding that number (80% of 30% is 24% by my perhaps antiquated arithmetic) and we get a total response rate approaching 94%.   I say, not bad, if those numbers are really on the up-and-up.

Are there any effective ways to prevent migraines through the use of drugs?

Prophylactic drugs have been tried in some migraineurs, especially those whose episodes are more frequent, severe, or of greater duration.   Classes of drugs include calcium channel blockers and beta blockers, which are essentially blood pressure medications, based on the idea that lowering blood pressure would relieve pressure on nerve endings in the brain.   Although use of these drugs is based on the perhaps discredited vascular theory, which we discussed earlier, some physicians continue to prescribe these antihypertensive drugs for migraine sufferers, and some migraineurs report that they get some relief from these drugs.   

The first FDA-approved prophylactic treatment option for migraines was Botox, which as we all know is botulinum toxin, used cosmetically to reduce, or perhaps totally obliterate, those little facial wrinkles that identify us as grown-ups.   Botox does this by blocking the receptors that trigger the contraction of facial muscles.   It basically works the same way in inhibiting migraines, by preventing the contraction of tissue around pain receptors in the brain. To do this takes about 30 subcutaneous Botox injections every 12 weeks at sites in the skin around the head.

(Please note the change from the previous version of this piece, in which I erroneously stated that the subQ Botox injections had to be given every month. That was an error, and Doc Gumshoe apologizes, and thanks the reader who spotted it and pointed it out.)

Botox is approved for individuals with documented chronic migraine episodes, meaning at least 15 migraines per month.   The success rate for Botox prophylaxis is moderate, reducing the incidence of migraine episodes in these chronic migraineurs by about 50%.   This may not sound like much, but to a person who has been getting slammed by a killer migraine every other day, cutting that down by half might be a big deal.   And, of course, the chronic migraineur can combine the prophylactic treatment with drugs that reduce the severity of any single episode.   (But I can easily see why migraineurs might shrink from a treatment regimen that requires 30 subQ injections into their scalps.)

A major prophylactic breakthrough occurred when the FDA approved Amgen’s Aimovig (erenumab) on 17 May 2018, which they are co-marketing with Novartis.   Aimovig’s mechanism is the inhibition of calcitonin gene-related peptide (CGRP), a molecule involved in triggering migraine attacks, which was discussed earlier in this piece.   Aimovig may be a valuable drug not only for persons with chronic migraine episodes, but for those with episodic migraines – a much larger patient population that has migraine episodes much less frequently than the chronic migraineurs.   Aimovig was compared with placebo in three clinical trials in this population, and the results were that treatment with Aimovig resulted in between 1 and  2½ fewer monthly migraine days.   Aimovig is given by means of a single self-injection every month, which is a considerable advantage over the 30 monthly subcutaneous injections required for every Botox treatment.   The most common side effects reported by patients in the Aimovig trials were injection site reactions and mild constipation.   As with Botox treatment, patients using Aimovig to reduce the frequency of their migraines can also use drugs such as triptans to reduce the severity of a single migraine episode.      

Another CGRP inhibitor is galcanezumab, given the brand name Emgality by its developer, Eli Lilly.   In clinical trials it has been demonstrated to reduce migraine incidence in patients who do not respond to prophylaxis with Botox.   Moreover, it is also effective in cluster headaches, which are different from migraines, and for which there has been no approved prophylactic treatment.    Cluster headaches are very painful, short in duration, affect a small area of the head, and tend to occur daily during a relatively short period of time, usually one or two weeks.

Results from the EVOLVE-1 clinical trial showed that prophylactic treatment with Emgality resulted in almost 5 fewer migraine days per month relative to baseline in patients with episodic migraines, while treatment with placebo reduced migraine incidence by 2.8 days per month.   (Stauffer VL. JAMA Neurol 2018;75(9):1080-1088)   Like Aimovig, Emgality is given by a self-administered subcutaneous injection once a month. 

More recently, other CGRP antagonists have become available.   Fremanezumab, trade-named Ajovy, from Teva Pharmaceuticals, is given by injection either monthly or quarterly.   In a clinical trial comparing three groups of subjects who had been experiencing around 13 headache days monthly, treatment with fremanezumab significantly reduced the average number of headache days per month compared with placebo-treated subjects, by approximately 4.5 headache days per month.    The percentage of patients with a reduction of at least 50% in the average number of headache days per month was 38% in the fremanezumab-quarterly group, 41% in the fremanezumab-monthly group, and 18% in the placebo group (P<0.001 for both comparisons with placebo).   (Silberstein S. N Engl J Med 2017;377;2113-2122)

Another CGRP antagonist, eptinezumab (Vyepti, from Lundbeck), received FDA approval for migraine prevention in adults on February 21^st, 2020.   It is administered intravenously every three months.   In a clinical trial enrolling over 1000 subjects, between 10% and 17% of those receiving eptinezumab experienced at least one migraine-free month at some point, and also more migraine-free months as time passed.   

The first oral CGRP antagonist, ubrogepant, trade-named Ubrelvy, was developed by Allergan under license to Merck, and is being marketed by AbbVie.   Ubrogepant received FDA approval on 23 December 2019.   It appears to be faster-acting than other CGRP antagonists and can be used for acute treatment.   In recent clinical trials, about twice as many patients receiving ubrogepant (19.2% and 21.2% respectively of the 50 mg and 100 mg doses) experienced freedom from migraine pain at two hours after dosing as did patients on placebo, 11.8% of whom experienced pain relief.   These results were judged to be highly significant (P < 0.002).   Ubrogepant also resulted in alleviation of the most bothersome migraine-associated symptoms.   (Scott LJ. Drugs 2020;80(3):323-328)        

The fact that effective treatment for migraines is provided by agents that inhibit the action of CGRP provides a certain amount of validation for the vascular hypothesis, namely that the pain in migraines comes from the pressure of dilated blood vessels on nerve endings, because what CGRP does appears to be to dilate those very blood vessels.   But perhaps it works in some other way that has yet to be figured out.   We’ll see!

I need to emphasize that the change from a treatment form that requires 30 subcutaneous injections per month into the scalp to treatments that can be given quarterly represents immense progress even if the overall results do not appear to be impressive.   

However, no currently-available migraine treatment as yet reliably provides relief from the great majority of migraine headaches.   It is not surprising that such a large segment of the migraineur population avoids any form of drug treatment.   The question is, what do they do instead?   Many individuals affected by frequent migraines simply do what they can to navigate around the life factors that seem to bring on their migraines – or, as they are called, migraine triggers.

What about these migraine triggers?

The list would include a large variety of food and drink, ranging from ripened cheeses which contain purines, to chocolate, and caffeinated or alcoholic beverages, various factors in the environment including perfumes and flickering lights; also (in women) the menstrual cycle.   A major factor is stress.   Migraine sufferers are thought to be highly responsive emotionally. Anxiety, worry, shock, and sadness can all release certain brain chemicals that lead to a migraine headache. (Ironically, the sense of release after a stressful period can also lead to migraines, which could be the cause of weekend headaches.)

The list is far from complete; in fact, I would question whether a complete list is possible, since migraine triggers vary enormously among individual migraineurs.   For every migraineur who is apparently exquisitely sensitive to chocolate, there will be another one who can feast on chocolate with impunity; for every migraineur to whom a glass of red wine is forbidden, there will be another who can drink red wine with no ill effects, but is laid low by a cup of coffee.   

As we look over the list of potential food triggers, it’s worth thinking about what’s in some of those foods that makes them risky for some migraineurs.   To the list of ripened cheeses (which could go on and on and on, of course), we should add preserved and smoked meats, which also contain purines.   Chocolate and coffee (and tea also) contain related methylxanthines; caffeine is a methylxanthine, but not all methylxanthines are the same; thus the migraineur who shuns chocolate may be able to drink coffee and vice versa.

And to the environmental factors, we should add the prevalence of erratic piercing flashing lights that we see everywhere these days – bicycles with pinpoint flashing headlamps that burn little holes in the retina, flashing lights on every kind of vehicle, whether responding to an emergency or racing to the corner deli for a cup of java, the flashing lights on the deli itself, flickering LEDs, and compact fluorescents.   These may pose threats not only to migraineurs, but to persons who are susceptible to seizure disorders.   

A presentation at the 2018 meeting of the American Headache Society cast some doubt on migraine triggers, suggesting that migraineurs are subject to that same post hoc propter hoc fallacy, which makes people think that if they experience a migraine after consuming chocolate or red wine, the migraine is caused by the red wine.   The eminent Dr Peter Goadsby points out that the migraineur may already be in the premonitory phase of the episode when he/she is exposed to the trigger.   Then, what the migraineur happens to drink or eat becomes associated with the migraine, and the migraineur succumbs to the fallacy.   Goadsby notes “Obviously, if you feel you’re in the premonitory phase that is not a night to go out, to stay up late, to find your favorite alcohol. It’s a night to be careful, to look after yourself, to prepare for the next day. This understanding is going to empower patients to get better control.”

With all possible respect to Dr Goadsby, the suggestion that migraine triggers are not as real as migraineurs feel them to be is somewhat arrogant.   What he and some of his colleagues are saying is that since the specific mechanism whereby those triggers produce a migraine has not been puzzled out, why then the whole migraine trigger thing may be illusory.   Doc Gumshoe concedes that scientists make leaps of logic of that sort from time to time, and this may be one of them.   It seems to me, based on the experiences of many migraineurs, that those triggers are real.

Here’s how Doc Gumshoe views the migraine treatment picture.   The scientists who are diligently looking for the essential cause of migraines have made some real progress, but that root cause remains elusive.   My guess is that while there may indeed be a single essential mechanism, there are many avenues to that mechanism.   As research is carried out, a picture will emerge showing the interaction of several different factors in the brain.   They will puzzle it out somehow.   

However, the scientists who are looking for treatment options that will deliver some benefit to the billion or so individuals on our planet who experience migraines are making considerable progress.   And as effective treatment modalities continue to emerge, that will also shed light on the essential cause (or causes) of migraines.   I look forward to the emergence of new, more effective treatment modalities to subdue migraines and ease the lives of migraineurs.

* * * * * * *

Putting together this piece provided Doc Gumshoe with something like a little holiday from COVID-19.   But there’s a good deal more about the pandemic, and I will swivel back to focus on it for the next installment.   That includes a possible explanation of how single virus can have so many different effects, as well as an attempt to peek forward and project how the whole thing is going to develop.   Stay well, be careful, and let me know what you are thinking.   Best to all, Michael Jorrin (aka Doc Gumshoe)

[ed. note: Michael Jorrin is a longtime medical writer (not a doctor), who I dubbed “Doc Gumshoe” many years ago — he writes health and medicine-focused columns for our readers a couple times a month, and though he does not generally cover investment ideas he has agreed to our trading restrictions. You can find his past columns here.]