Category Archives: Clinical

 (Proposed) World Headache Society’s Definition for Refractory Migraine

Lawrence Robbins, MD


To expand the current description of refractory migraine, the World Headache Society advocates the use of both simple and complex definitions. Simple would be for the general use of patients and support groups, and complex for research and clinical purposes. These definitions include the roles of preventive and abortive medications, non-medication treatments, medication overuse headache (MOH), and a refractory scale to rate severity.  The complex definition provides criteria for the categorization of responses to both abortives and preventives based on the availability of migraine treatments in different countries. It is suggested that refractoriness is defined as failure of adequate trials of at least 3 classes of preventives or 2 classes of abortives.  For countries with limited access to both preventive and abortive therapies, the patient should have failed at least half of the available preventive classes, or all of the classes of the available abortive therapies. The rationale behind the definitions is discussed in the subsequent sections.

A. Introduction

When an individual has persistent headaches that fail to improve after a trial of the standard treatments, the term “refractory migraine” is often used in clinical practice.1   This term was coined by Reisman in 1952.2 Since then, a number of definitions for refractory migraines have been proposed.3,4,5,6,7 However, the current definition is appropriate primarily for countries where there is a wide array of treatments available, including onabotulinumtoxinA and CGRP medications. There is no mention in the current definitions of abortive approaches. Moreover, the role of medication overuse headache (MOH) is unclear in current definitions. There is no scale to separate milder patients from the more severe refractory migraineurs. It is also noted that current definitions focus on refractory chronic migraine. We have chosen to define refractory migraine.

This paper outlines the proposed definition of refractory migraine and the rationale behind the definition. In addition, other topics such as abortive medications, MOH, and a refractory scale have been included. To expand the current definition of refractory migraine, we would like to suggest both simple and complex definitions. Simple would be for easy general use, and complex for research and headache specialists. In the future, a panel of headache experts from the regional directorates of the World Headache Society will publish a consensus document.

B. Objectives for a revised definition

 To standardize terminology and agree on working definitions in order to:
– provide a clear definition of refractory migraines for:

  1. Headache specialists
  2. Researchers in headache medicine
  3. All clinicians and allied healthcare professionals
  4. Patients and caregivers
  5. Policy makers and patient advocacy groups

– classify headaches in terms of severity and disability across the lifespan (pediatric, adult, elderly)
-to include responses to abortives as well as preventive therapies

C. Definition of Refractory Migraine

Simple definition:
The migraines have not been adequately controlled by medications or non-medication approaches.

Note: This definition is drafted for the general use of patients, primary caregivers and patient advocate groups.

Complex definition:
The migraines have not been adequately controlled by medications or non-medication approaches (non-pharmacological). 8,9    

The migraines may be refractory to preventives, abortives, or to both. Not all patients have required preventive medications. If they have only been taking abortives, but these have failed, they do have refractory migraine (but just to abortive therapies). In addition, MOH will have been addressed prior to designating the patient as having refractory migraine.

Migraine is defined according to the International Classification of Headache Disorders-3.  In addition, migraine mimics and secondary migraines have been excluded,  as discussed in the World Headaches Society’s WHIS-MCH1 Classification Group 1, Syndrome of Migraine.

Note: This definition is drafted for the use of clinicians, allied medical professionals, and researchers in the field of headache medicine.

 Explanatory Notes

 2.1 Non- medication approaches

 Non-medication approaches have failed to achieve adequate relief. Not all patients are able to utilize most of the non-medication therapies, but attention to the usual lifestyle changes should have been attempted. At least one of the following measures should have been utilized: meditation, biofeedback, other relaxation approaches, psychotherapy, yoga, acupuncture, massage, physical therapy, and others.10,11,12

 2.2 Preventive medications or preventive injections

For patients who have had access to almost all migraine medications, including OnabotulinumtoxinA and CGRP monoclonal antibodies:      

The preventive approaches have failed to reduce the impact of the migraines by at least 50%, as evidenced by a headache diary.13,14 The patient should have failed on at least 3 classes of migraine preventives.

Failure was either inadequate relief from an adequate trial of the medication for at least 8 to 12 weeks or discontinuation due to adverse effects or ineligibility due to co-morbidities. The classes of preventives include (certain) anticonvulsants, antidepressants, and antihypertensives. In addition, the patient will have failed on onabotulinumtoxinA and/or a CGRP preventive (injection or oral).

Preventive medications: For patients with limited access to certain migraine medications

The preventive approaches have failed to reduce the impact of the migraines by at least 50%.  The patient should have failed on at least half the classes of migraine preventives that are available. Failure was either inadequate relief from an adequate trial of the medication for at least 8 to 12 weeks, or discontinuation due to adverse effects. The classes of preventives include (certain) anticonvulsants, antidepressants, and antihypertensives. In addition, the patient will have failed on onabotulinum toxin A and/or a CGRP preventive (injection or oral), or trials of non-medication therapies such as non-invasive neuromodulation, acupuncture, yoga or CBT.

 2.3 Abortive therapies

Abortive therapies: For patients who have access to almost all abortives, including gepants

The abortives have not provided consistent relief at least 50% of the time (trial in at least 4 consecutive headaches). Relief is defined as pain-freedom (or “near” pain-freedom) at 2 hours, after medication overuse headache has been addressed. 15,16,18 Alternatively the medication may have been discontinued due to intolerable adverse effects. The patient should have utilized simple analgesics (paracetamol and NSAIDs) and at least 2 of the following categories: triptans, gepants, DHE, or injectables (ketorolac, etc).

Abortive therapies: For patients with limited access to certain abortive medications.    

Refractoriness may be defined as non-responsiveness to all of the available classes of abortive therapies.

NOTE: It is important to note if the patient is refractory to preventives, abortives, or both preventives and abortives.

 2.4 The Role of Medication Overuse Headache (MOH)

Medication overuse headache (MOH): The patient should have been assessed for MOH. MOH is defined according to ICHD-3 with the modifications as follows:

  1. It is important that MOH not be conflated or confused with medication overuse (MO)
  2. To determine whether MOH is truly present, a careful history regarding the offending medication must be obtained. Based on the history and assessment of headache diaries, it should be more likely than not that the offending medication is actually triggering more migraines. Ideally, the subsequent medication should be withdrawn, and the effect on the patient’s migraines observed. This is not always possible.
  3. After observing the results of the offending medication having been discontinued, a definite determination of MOH may be made. If it is determined that the patient is most likely is suffering from MOH, the designation of refractory migraine will be withheld until the MOH situation is resolved.

2.5 Refractory Migraine Rating Scale:

It is useful to separate patients into mild, moderate, and severe refractory. This is helpful for research purposes. In addition, our clinical approach and expectations are different for a patient with mild refractory migraine versus severe refractory migraine.18,19

Refractory Rating Scale for adult patients, age 20+:  The scale consists of eight items, with 10 possible points. Points are added if the patient is:

Refractory to preventive approaches

2 points

Refractory to abortive medications

2 points

Duration (number of years) of migraine occurrence; if greater than 10 years

1 point

Number of headaches per month; if 25 or more days, on average

1 point

Two or more diagnosed comorbid central sensitization syndromes (irritable bowel syndrome [IBS], chronic regional pain syndrome (CRPS), temporomandibular joint disorder [TMD], fibromyalgia, chronic pelvic pain, burning mouth syndrome); in addition: chronic fatigue syndrome, or visual snow

1 point

 Psychiatric comorbidities, whether a severe Axis I disorder (ie, an affective disorder) or any definite Axis II disorder (ie, a personality disorder), as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5)

1 point

Disability (work/school and/or home )

1 point

Medication overuse headache (not simply medication overuse)

1 point

After totaling the points, the scale helps clinicians to categorize patients as follows:
2 to 4 points= mild refractory migraine
5 to 7 points= moderate refractory migraine
8 to 10 points= severe refractory migraine.

Refractory Migraine Rating Scale for Adolescents, ages 11 to 19:

 The point system for the adolescent patient would be as follows:

Refractory to preventives (which may include onabotulinumtoxinA)

1 point

Refractory to abortives

1 point

Headache occurrence greater than one year

1 point

Number of headaches per month; if 25 or more days, on average

1 point

Significant comorbidities; if at least one is present (IBS, TMD, fibromyalgia, or chronic fatigue)

1 point

Psychiatric comorbidities: severe Axis I (affective disorders), or a strong indication that Axis II (personality disorders) may be present

1 point

Disability defined as an inability to go to school for at least 2 months due to headache (either homebound, or a greatly modified schedule), or a significant decrease in functioning

1 point

Severe family dysfunction, which may include personality disorder pathology in the primary parent (usually the mother)

1 point

With this scale, a total of 8 points would be possible, ranking as such:

   2 to 4 points = mild refractory migraine.
   5 to 6 points = moderate refractory migraine.                         
   7 to 8 points = severe refractory migraine.

Future Perspectives and Conclusion

This is a continuous work in progress. We have attempted to revise and add to existing refractory definitions. Our primary changes include: including abortives in a refractory definition, separating a simple from a more complex definition, adding a section that applies to patients with limited access to more advanced approaches, adding to the existing MOH definition, and adding a refractory rating scale for adults and adolescents.

In the future, we may use biomarkers to identify refractory patients, but until then we must use our clinical criteria.

Key points


Simple Definition

The migraines have not been adequately controlled by medications or non-medication approaches.  

Complex Definition of Refractory Migraine

>The migraines have not been adequately controlled. Non-medication approaches had not sufficiently alleviated the headaches. It is important to note if the patient is refractory to preventives, abortives, or both. Not all patients will have required preventive therapies.

>If preventives have been used, they have failed to reduce the impact of the migraines by at least 50%. At least 3 classes of preventives will have had an adequate trial.

>Abortive medications will have failed to achieve adequate relief of 50% for at least 4 episodes.

>Medication overuse headache will have been adequately addressed.

>For countries with limited access to both preventive and abortive therapies, the patient should have failed at least half of the available preventive classes or all of the classes of the available abortives.


Committee Chair: Dr. Lawrence Robbins

Members: Dr. Pravin Thomas, Dr. Paul Emmanuel Yambao

Permission has been obtained from the co-authors to reproduce this article on Refractory Headache definition in the SPS newsletter.  Dr. Thomas is the founder (and directs) of the WHS, and Dr. Robbins is a Vice President. The permission comes from Dr. Pravin Thomas. 


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Evolutionary Medicine: A Focus on Migraine and Psychiatry

Lawrence Robbins, MD

 Evolutionary Medicine is a growing, vital, fascinating and relevant area. I use it daily in my practice, to explain to patients (such as the evolutionary reason for anxiety, why we have so much neck and back pain, why we suffer pain and mortality with childbirth etc…) it should be taught in our medical, nursing, and physician assistant (PA) schools. We could avoid problems by studying evolution.  How best to use antibiotics, and how avoiding blocking certain compounds that are crucial for 400 million years such as CGRP, which certain migraine drugs block, are two examples of how understanding evolution could benefit patients. We ignore evolution “at our peril”.

A Bit O’ History

  • Darwin thought along evolutionary lines: ERASMUS DARWIN, that is… (1790) Erasmus was the grandfather of Charles. Lamarcke (about 1805) built on his ideas. Lamarcke had the right idea (but thought an acquired trait during one’s life could be directly inherited… he believed in “spontaneous generation”)
  • Later in 1858, Charles wrote “On the Origin of Species”. He was hurried along because of Alfred Wallace; they admired each other. Similar to Rosalind Franklin of DNA discovery, Wallace has been unfairly forgotten.

Early objections to evolution (my main thesis as an undergrad) were mainly along religious grounds, and also that early proof was lacking. Although The religious arguments persisted, within 15 years evolution was scientifically accepted.

Why Study Evolution?

  • Goal of medicine is to improve health and prolong life.
  • Evolutionary medicine goals include to:
    • Help develop safer treatments, such as our new CGRP meds to prevent migraine which are possibly dangerous.
    • Change modern behaviors. Historically, we had a healthier diet, and constantly exercised, for 99% of our human existence.
    • Learn to use medications in healthier ways, such as how to manage antibiotics.
    • Help clinicians explain to patients the evolutionary reason for their conditions, such as anxiety, depression.

Proximate vs. Evolutionary

  • Proximate explanation = the nuts and bolts, such as neurochemistry, physiology, etc.
  • Evolutionary = WHY something came about
  • Proximate = a mechanical explanation
  • Evolution = the engineering design
  • Ontogeny = proximate (mechanical, “nuts and bolts”) development of an organism from fertility to egg to adult
  • Phylogeny = evolution and history of a species

Natural Selection

  • Natural selection (NS) depends upon variation.
  • NS operates mainly at the level of the gene.
  • NS involves phenotypic variations driving genotype and phenotype changes over generations.
  • Within a population, variation leads to some individuals being better suited to the environment than others. This results in adaptive changes.
  • Natural selection is going on today; as little as 8,000 years ago, nobody had the genes to digest lactase; now, the genes for lactase are present in over 70% of Northern Europeans. Even by Roman times those genes were becoming more common.

Asking the Right Question

  • The right question (Nesse/Williams): Why are we so vulnerable to various diseases?
  • The wrong question: what evolutionary advantage does each disease have? (yes, they may have advantages, but often they do not).
  • Albert Einstein said, if given 60 minutes to solve a problem, he will take 55 minutes to come up with the right question.
  • Jonas Salk: “Solutions… they come through asking the right question, because the answer pre-exists”…

6 Principles of Evolutionary Medicine

  • Randolph Nesse pioneered much of this thinking: (Nesse and Williams):
    1. MISMATCH: our environment has changed, we are adapted for a radically different (ancient) environment.
    2. TRADE-OFFS: many (most) aspects of human anatomy and physiology involve trade-offs.
    3. EVOLUTION cares about reproduction and propagating one’s genes; it DOES NOT CARE about: health, happiness, longevity (except for possibly the “grandmother hypothesis: nurture and epigenetics”).
    4. PATHOGENS can replicate much faster than humans; hours versus our 18+ years. Pathogens will usually win the evolutionary arms race.
    5. DEFENSES: many symptoms are often defenses, not diseases (fever, nausea/vomiting, cough, diarrhea).
    6. NATURAL SELECTION and evolution are LIMITED; there are constraints on what selection can do; evolution tinkers, it does not invent.

Mismatch with the Environment

  • Ten to twelve thousand years ago we began to cultivate agriculture.
  • We morphed from hunter-gatherers (H-G) — more accurately called “forager-gatherer-fisher-hunters” — to agriculture-based societies.
  • Changes in our environment include:
    • agriculture
    • a move towards dense, urban populations
    • artificial light, less sunlight, & light at night
    • Houses
    • Reading
    • Pollution
    • sterile food/water
    • solo sleeping
    • bottle feeding
    • Antibiotics
    • other medicines
    • sleep changes (less sleep)
    • steady food with less food insecurity and less fasting
    • heating and cooling
    • long-term marriage
    • birth control
    • mass media and social media
    • louder sounds
    • change in diet to high starches (beginning 14,000 years ago): led to many problems
  • Approximately 50% of diseases are strongly influenced by environmental changes (mismatch with our previous environment)

Evolution and Migraine

  • Migraines increased as we moved to more northern latitudes. Low vitamin D levels and the TRPM8 gene play a role. TRPM8 is linked to decreased sensitivity to both cold and migraine.
  • Migraine due to mismatch with our modern environment, including increased light, sound, stress, immune response (possibly tied into ridding ourselves of worms/parasites), lack of exercise, urban density (and an increase in infections), poor sleep, changes in diet, pollution, electronics and social media, etc…
  • Migraine may have occasional evolutionary advantages such as an enhanced immune response could be helpful in fighting certain infections. it is speculated that the rates of mating and fecundity among migraineurs may be increased, and more research is needed. In the past most people died of infections. If one is laid up with a migraine when a virus sweeps through, the migraine may enhance survival.
  • Why migraine is much more common in women is unclear. Migraine often decreases during pregnancy, offering a small evolutionary incentive for more pregnancies.
  • Hunting/fishing were often done more by men; migraine may pose disadvantages for these activities.
  • Women did more of the foraging; migraine may not have as much of an effect on foraging, although this is unclear.
  • Why does migraine only affect humans? It may be that our ancient human brainstem has difficulty coping with a newer cortex that is vastly enlarged. Higher cortical functions may add to our continued vulnerability to migraine.
  • Migraine could be a defense mechanism against excessive stress, noise, or light.
    • Migraineurs have an enhanced sensitivity to smells; this may be protective from toxins or viruses entering the CNS. Vomiting from a migraine may remove toxins.
    • Women with migraine (probably) have a lower incidence of Type 2 diabetes.                                                                                    
    • Activating the trigeminal nuclear complex could be protective to the migraineur.
  • If a migraineur has 100 migraines in a year, and just one protects from harm, the trade-off may be worthwhile. Evolutionarily, the cost of migraine may be inexpensive.
  • Headache and pain are adaptive. Being still in bed may help with repairing damaged tissues.
  • As mentioned, mismatch with our modern environment, with radical changes over 12,000 years, is a primary driver for the increase in migraines.
    • Cultural changes (social media etc.) also may play a role.
    • The elimination (past 140 years) of worms/parasites in our GI systems has led to an increase in autoimmune illnesses. Migraine is probably (somewhat) autoimmune.

Migraine, Evolution, and our CGRP Therapies-

  • CGRP monoclonal antibodies to prevent migraine were introduced 2018. They are effective, but these have many short term adverse effects (in the 1st 3.5 years, 50,000 adverse events reported to the FDA, and 7,000 serious ones).
    • We do not yet know long term effects. CGRP has been in animals for at least 350 million years and is ubiquitous throughout our body. Blocking CGRP for years (or decades) ignores all of it’s numerous evolutionary advantages. If we paid attention to evolution, we may not have pursued the avenue of blocking CGRP.
    • We ignore evolution at our peril!

Further reading and YouTube viewing on Evolutionary Medicine:

There are excellent books, but I recommend searching YouTube: many outstanding talks on evolution and medicine

  • Books: Why We Get Sick by Nesse and Williams, Human Errors by Lents, Good Reasons for Bad Feelings by Nesse, Evolution and Medicine by Perlman
  • Robert Sapolsky is a marvelous author and speaker (many talks on YouTube: he was Scientist of the Year (U.S.) and has a newer book out, “Behave” that incorporates evolution and behavior
  • Principles of Evolutionary Medicine by Gluckman et al., Evolutionary Psychiatry by Brune, The Third Chimpanzee by Diamond, Chaos and Life by Bird, The Evolution of the Human Head by Lieberman, Evolution In Health and Disease by Stearns et al, The Lives of the Brain by Allen, Sapiens by Harari, The Riddled Chain by McKee, Evolutionary Medicine and Health by Trevathan et al.


  • An excellent lecture is “An Evolutionary Model of Depression” by Markus Rantala
  • YouTube: There are hundreds of excellent lectures and discussions.
    • Randolph Nesse has a plethora of videos and interviews; Yale Medicine and Steven Stearns has a series of excellent videos; Nathan Lentz is outstanding; Robert Sapolsky as mentioned above, and many others.

Evolutionary Psychiatry (EP)

  • Anxiety and the “Smoke Detector Principle”
    • At the watering hole on the Savannah, if the chance of getting eaten is even 1 out of a thousand, it is worthwhile to run away every time; this is “adaptive”
    • However, if we start having panic attacks for no reason, this is “maladaptive”… the margins between adaptive and maladaptive can be blurry… and it all depends on the context in which the behavior occurs.
  • The stress response is a product of millions of years of selection. The system is usually adjusted and turned off due to its costs. These adjustments include a minimized immune response during stress along with an increased metabolism.
  • Even in fish, timid fish survive predation more than bold ones…
  • Even now, evolution is occurring: red squirrels around Chicago are disappearing, as they are bolder than the grey squirrels, and don’t run away from cars. The timid grey squirrels are surviving
  • Many behaviors are observed in humans and primates, and all the way back to fish or even fruit flies! Many animal behaviors do not change from genus to genus.
    • When emotions become maladaptive, they become a “psychiatric illness”
    • Anxiety costs energy, due to catecholamine release and cortisol depletion. Energy (or the lack of) and ATP governs much of animal behaviors and evolution.
    • Chronic stress and anxiety become maladaptive, with deleterious effects.
    • Phobias can be viewed as maladaptive forms of what would be healthy adaptive thoughts in a different environment. Phobias arise out of a perceived danger from attack, trauma, or predation. What might be a reasonable response in a context 2 million years ago is unreasonable now. We are unlikely to have problems from snakes, spiders or sharks, but these phobias persist…
  • Adolescent behavior of pushing, attention seeking, impulsivity, and aggressiveness can be an advantage for mating and reproduction. Remember, evolution cares not for how happy you are, or how long you live. Evolution cares most about propagating genes.
  • Risk taking can also help in food acquisition.
    • Male risk taking (peaks in adolescence) succeeds evolutionarily. It leads to more reproduction, but also contributes to many earlier deaths.
    • At age 20 (and most other ages), for every 100 women who die, on average 350 men die, partly due to risky behaviors. This number varies between countries. These risky behaviors lead to more procreation (which is the purpose of evolution), but also leads to death. Men are also more vulnerable to certain diseases. Men are 2 to 3 times more likely to die of cancer or heart disease. An increase in procreating, but dying earlier, is a classic trade-off.
  • ADHD could possibly have adaptive survival benefits. In the forest, it could conceivably be beneficial to be unfocused and constantly looking around. However, it is more likely that ADHD is not very beneficial, but rather it is one of many illnesses that evolution simply cannot delete out of our genome. Schizophrenia is another such illness. One percent of people are schizophrenic in almost every country. Schizophrenia results in no evolutionary advantage for survival.
  • Certain personality disorder (PD) traits (aggressiveness, salesmanship, paranoia, alpha behaviors, and the “charming- seductive” behaviors) can result in increased mating and reproduction. This is part of the reason why PDs persist. The other reason that these genes persist is the plethora of different genes involved in PD pathology. Evolution has no easy way to delete these genes.
  • DEPRESSION: The different symptoms can be adaptive — if fighting an alpha male, submissive and depressed behavior may enable immediate survival. Low mood may allow an organism to recover from an infection more easily by not moving about. Depressed people may show little movements of the eye and mouth region, avoid eye contact, speak softly, and remain socially inactive. These all have advantages in certain contexts.
  • In a situation where appeasement is necessary, and inferiority or defeat is present: the non-verbal behaviors of depression may lower aggression by others. Catatonia may be an extreme example of ancient defense mechanisms.
  • Dominance, submission, and social hierarchy are inherent in most primates (and other animals, going back 400 million years). The winner and loser in a clash ideally both remain within the group. In ancestral environments, exclusion would have meant death.
  • Human life is dependent on a complex web of interactions with other humans, more than in other primate species.
  • Why do women have more depression than men? Outside of the proximate “nuts and bolts” explanations, evolutionary sex differences play a role. Women (more than men) depend upon social support. Women have had less ability (for several reasons) to leave a bad relationship/marital situation, with depression as a consequence. This may go back to ancestral times.
  • Many theories as to why we become depressed have been put forward.
    • Early work focused on infant attachment.
    • Negative life events may trigger low mood or depression, and also loss of social status. Hunter-gatherer societies experience the low mood but not nearly as much of the depression. Depression is rampant in Western societies.
    • These theories are outlined in the excellent book by Randolph Nesse, MD: Good Reasons for Bad Feelings (2019)
  • Depression is much more prevalent in Western societies
    • Depression (and anxiety) has increased from 2008 to the present; probably mismatch with the environment (social media, smartphones, pollution, etc.) and world stresses (pandemics, politics, war)
  • As mentioned, little depression is observed among various hunter-gatherer societies, and also among the Amish.

 EP — Depression, Inflammation and evolution

  • Inflammation plays a role in depression; our “modern’ diet plays some role in this…
  • Western society has more inflammation than hunter-gatherer societies
  • Our lifestyle and subsequent mismatch with the modern environment are factors
  • GI worms/parasites downregulate our neuroimmune response; since ridding ourselves of these in the past 120 years, inflammation has skyrocketed!
  • A “depression symptomatic” approach fits into evolutionary thought: the idea is that depression is a description of a number of different symptoms but not a “disease” itself. There is some evidence that simply asking about “low mood” is just as accurate for diagnosing depression as using DSM-5 criteria. A MDD diagnosis is not that helpful in guiding specific treatments.
    • The “depressive symptomatic” approach evaluates the varying symptoms, each of which can be treated. The symptoms influence each other in a feedback loop: for instance, insomnia causes fatigue, which increases low mood, which then exacerbates insomnia.
    • If we perturb one part of this system, the system will read just itself into a new homeostasis: if we decrease the insomnia, the fatigue is lessened, and then the depression may be better.
  • Each particular symptom could be adaptive in an evolutionary sense; the symptom becomes maladaptive if it is pathologic and causes undue distress, such as panic attacks. Adaptive vs. maladaptive varies depending upon the environment and context in which it occurs.
  • Sadness/emotional pain could be adaptive in that they lead to avoidance of actions that may result in more losses.
  • Crying elicits empathy and support from other group members. Exclusion, real or threatened, from a group may lead to depression. Loss of social status or hierarchy triggers depression.
  • Fatigue helps conserve energy and may be adaptive.
  • Seasonal affective disorder (SAD) may help to conserve energy in winter. In winter if a primate hunkers down, possibly due to low mood, and does not go out in the cold, energy is conserved.

EP and Mania

  • Mania may represent the pathologic extreme of dominance behaviors. Dominance and risky behaviors may lead to increased mating and reproduction (the goal of evolution).
    • Mania could also be a compensatory mechanism to view the world as less threatening.
  • Hypomania/hypersexuality = may result in increased mating.
  • Mixed states: one theory — mania is generated more from the cognitive/cortex level, and appeasement/depressive behaviors from the reptilian (older) brain.
  • In dysphoric mania, evolutionarily the mania could offset that pervasive hypervigilant fear that is so often present.

EP, cont…

  • Selection favors traits that promote fitness in our social environment such as: cooperation, reciprocal altruism, the ability to interpret actions of others, and also to detect freeloaders within the clan.
  • Altruistic behavior lowers group stress, increasing survival of all group members.
    • What may look altruistic may actually be survival of the individual (the famous Wild Kingdom Wildebeest episode)
  • An increase in cortical neurons, and acquisition of language, resulted in more complex group behaviors.
  • Human behavior also involves mating choice, kin selection, social group living, etc. For more on human behavior, check out Robert Sapolsky’s books (particularly his book “Behave”) and YouTube talks.
  • Schizophrenia and bipolar share many genes, spread throughout the genome. Autism and schizophrenia also share similar genes.
  • The multitude of genes, spread throughout, is one reason evolution cannot easily delete “bad” genes. Mutations also play a role in creating “new” psychiatric illness. When many genes are involved it renders it impossible to cure these illnesses through any type of “gene therapy”.
    • There are exceptions, where a cure is conceivable, such as Huntington’s (a specific CAG repeat)
  • For men, appeasement and submission do NOT pay off with increased mating. However, they may enhance survival. The differences in male vs. female depression may go back millions of years.
  • For men, social status = crucial towards mating and reproduction. Higher social status = more mating.
  • Lack of social support from elderly kin leads to increased risk for depression.
  • We are clannish by nature: “The oddity effect”: animals don’t associate or align with phenotypically different individuals. This goes back to fish, birds, mammals and even plankton! Clannish nature may contribute to “otherism”, and possibly racism as well.
  • This may be the origination of human bullying (“appearance-based bullying”), and helps to explain xenophobia.
  • Within a group, those that look the most like the group tend to be the worst bulliers.

 Vasovagal syncope is probably adaptive. It is paradoxical: fainting in the face of perceived danger. The syncope could be adaptive in certain dangerous situations, so as to survive as a younger adolescent. In primates, when fighting a stronger alpha male, it is adaptive to faint and then have a chance at survival.

  • Vasovagal syncope is observed in adolescents of other primate species.
  • Humans are sensitive to early stress or trauma. As with most behaviors, this is true for other species as well. Even fish are sensitive to early stresses! In primates the effects of stress begins in utero (if mom is stressed, cortisol changes result and this greatly affects the fetus). The vital amygdala-prefrontal cortex connectome is greatly influenced in utero and in the first year of life.
  • Aggressive and alpha behavior can be learned (as demonstrated by fish: the fish that lost the battle with an alpha fish, then was allowed to watch the alpha fish interact with others, subsequently learns to act like an alpha fish).
  • Taking an ethological (observing behavior in various species) approach, depression may be observed in most species.
  • These species include primates, voles, rats, and (There is an excellent YouTube talk on this: An Evolutionary Model of Depression, by Markus Rantala)
  • The pelvis changes that resulted from going bipedal contribute to our difficulty with childbirth. Human mothers have more childbirth pain than other species. Human infant and/or mother mortality has been 10 to 20%. The baby has to rotate and flip. Our large skull size also contributes to the childbirth difficulties. We are born relatively immature, as compared to other primates, partly due to our large head: we are born earlier than is ideal.

President’s Message: Running Headlong into what You Thought Was Behind You

Harry J. Gould, III, MD, PhD

With the FDA’s blessing in mid-December on the administration of vaccines for COVID-19 and subsequent indications of downward trends in the rate of infections, hospitalizations and deaths associated with the virus came a feeling that the worst of the pandemic was past and we were on a return path to recover normalcy. Even with large numbers of individuals that chose not to be vaccinated, the falling numbers reflecting the impact of disease were encouraging and many businesses, organizations, and individuals began to abandon mitigation practices, i.e., social distancing and masking, and began returning to former practices and patterns of behavior. In-person visits in clinical practice began to replace the virtual platforms and we were again able to apply our mitigating strategies for reducing medication misuse, abuse and diversion, thereby lessening some of the provider’s anxiety associated with the impaired ability to identify potential problems related to opioid management.

Indeed, the Southern Pain Society’s (SPS) planning committee for the 2021 Annual Meeting, upon reviewing the trends in societal response to the vaccines, was cautiously optimistic and was looking forward to being able to hold our annual meeting in-person. Despite the committee’s best efforts to plan and deliver an informative and thought-provoking meeting that might also serve as an indicator that we were on the mend, the trend in disease statistics foreshadowed a lack of support for these efforts.  Due to the establishment and spread of variants of COVID-19 in the population, the rate of infections, hospitalizations and deaths shifted and by mid-August had returned to, and in many places surpassed, levels that had been recorded at the peak of the first wave of the pandemic.  By the late August, elective procedures and in-person appointments in clinics were again being replaced by virtual visits.  As a professional organization, the SPS could no longer be reasonably certain about ensuring individual safety for our participants, chose not to put individuals at risk of becoming seriously ill and postponed the 2021 meeting; perhaps a fortuitous decision in light of the additional complications imposed by Hurricane Ida.

The distractions of the last 18 months have emphasized the importance of maintaining and expanding efforts to improve patient safety and reliably delivering appropriate and effective care even in the face of adversity. As the pandemic continues, the SPS is expanding efforts to maintain and offer new opportunities to share ideas and express concerns, challenges, and potential solutions for the challenges facing our patients and practices. In offering opportunities to support scholarly activity and communication, like the recent virtual forum for abstract presentations.  We hope to encourage those with the wisdom and experience accrued through years of experience and those new to the field of pain medicine to come together and share ideas and experiences and hopefully create a forum for inquiry that will foster the pursuit of a better understanding of complex condition we strive to treat; its proper assessment; and optimal treatment options supported by evidence necessary for making the most appropriate management decisions.  I encourage you to follow our newsletter and postings on social media for opportunities as we continue to monitor the pandemic and set our sights on the future when we will be able to meet again with the pandemic behind us, even stronger than before. 

Personality Disorder Patients in a Pain Clinic: Recognition and Management

Olivia Lee and Lawrence Robbins, MD

Approximately 9.6% of Americans have a personality disorder.1,2  These are common conditions, and all medical professionals encounter patients with such disorders in their practice. Early identification of this group of patients is ideal.  In the following we discuss how patients with these psychiatric conditions may present to an outpatient pain clinic, and we provide suggestions for management.

Introduction to Personality Disorders IN a PAIN Clinic

Personality disorders (PD) are characterized by abnormal behavior and experience that affects a person’s functioning. The DSM-5 defines 10 personality disorders separated by shared traits into three clusters: cluster A (characterized by odd, eccentric behaviors), cluster B (characterized by dramatic, erratic behaviors), and cluster C (characterized by anxiety and/or fear).3 Like many other psychiatric conditions, personality disorders exist on a spectrum, with some patients coping with more mild forms, and others suffering more severe diagnoses that wreak havoc on their lives and relationships.

Cluster A: paranoid, schizoid, schizotypal

Cluster B: antisocial, borderline, histrionic, narcissistic

Cluster C: avoidant, dependent, obsessive-compulsive

These names of various PDs make little sense, and should be revised. Not every presentation fits neatly into one diagnosis, and patients with PD often show features of different personality disorders. Some personality disorders are inherently more difficult to manage than others. The more challenging PD features include lack of insight, distrust of providers/therapy, disregard of social norms, sense of entitlement, manipulation, emotional outbursts, impulsivity, violent behavior, splitting, and exploitation. Comorbid substance abuse is common and compounds the dysfunction.4

While most patients with these conditions are not overly aggressive, there are some situations that can quickly deteriorate. Early detection of PD pathology helps the patient and family, and also may protect the provider. These early signs vary depending on the type of personality disorder.  The more severe PDs include antisocial, borderline, narcissistic, and paranoid.

Feeling uncomfortable or threatened while seeing a patient may be a clue that we may be dealing with a person with PD. Providers who encounter these patients commonly describe feeling the presence of a PD during the encounter; in troubling cases, the hostility, agitation, manipulation, and egocentrism are usually evident in the patients’ dialogue. Additional supportive evidence of a severe PD include constantly changing providers (due to mistrust or dissatisfaction), excessive demands, splitting, medication misuse, and threatening behavior (including baseless lawsuits). If the provider feels angry, manipulated, or “set-up” after the encounter, those are clues that they may be dealing with a PD.

Many of the more severe PD patients flip between victimhood, persecutor, and savior. When they turn the severe anger on someone (persecutor) it often does not end well.

PD characteristics may have an evolutionary advantage in procreating genes. Evolution does not care if we live long, or how happy we are. Evolution is mainly concerned with passing on our genes. The aggressive type A “alpha” male, who may also be charming, mates more often, fulfilling the goal of evolution. These personality characteristics are found in borderline, narcissistic, and antisocial personalities.

The more severe PD  types are as follows:

 Paranoid Personality Disorder (PPD)

Patients with PPD are characterized by pervasive suspicion and mistrust of people and the world around them. Frequently, they appear secretive and are reluctant to confide in others, including physicians. In relationships, patients with PPD may view themselves as being mistreated, exploited, or harmed, and often doubt the loyalty of even those closest to them. They tend to be ultra frugal. When their interpersonal suspicions cross over into the patient-provider relationship, it may lead to poor compliance and follow up of the patients. Patients with PPD are further complicated when they have a history of hostile outbursts or violent behavior in response to their paranoid perception of the world. Many of the spree killers have PPD.

Antisocial Personality Disorder (APD)

Patients with APD have little regard for the rights of others and engage in irresponsible or criminal behaviors. The pediatric equivalent is conduct disorder, which may morph into APD once the child reaches adulthood. These patients are irritable and impulsive in demeanor, and generally take part in exploitation, violence, or fraudulent activity. Patients with APD are at greater risk of alcohol use disorder due to their impulsive nature, and co-occurrence complicates management.4

Borderline Personality Disorder (BPD)

BPD is characterized by emotional instability, poor self-image, and pervasive abandonment fears. Like patients with APD, these patients typically demonstrate impulsiveness and coexisting problems with drug abuse, and other addictive behaviors may occur.4 There are usually longstanding feelings of emptiness or severe loneliness, extreme mood fluctuations, and chronic suicidal ideation. The suicidal feelings increase during the late twenties and thirties ages, when family and friends have drifted away. If a person with BPD is hospitalized, they often have increased suicidal thoughts upon leaving the hospital. When under stress, these patients can become paranoid. Characteristically, patients with BPD demonstrate splitting, a defense mechanism in which people are seen in either an all negative or all positive light. There is no “grey” or middle ground. Patients with BPD often produce chaos and drama for no reason. There is a sense of entitlement, with little empathy for others. Most (but not all) people with BPD lack insight. In a medical office they may present as a victim, but there are times the person with BPD will become angry with the staff and provider.

Narcissistic Personality Disorder (NPD)

NPD is one of the less common personality disorders and is typified by a someone who sees themself as better than others. The patient is grandiose and exhibits a lack of empathy. The person carries an inflated sense of self-importance. Many of these features overlap with BPD. There is a deep sense of entitlement, and they constantly require admiration and special treatment. As with most PDs, patients with NPD have demonstrated a limited response to psychiatric therapy. There is usually a  resistance and hostility towards intervention, and patients prematurely terminate the therapeutic relationship.5

Physicians have a right to discontinue treatment when the pathology exhibited by the patient is beyond their scope of practice, is disrespectful, or is threatening. Providers who encounter severe PD patients should evaluate whether their practice can safely manage that type of person. The staff does not deserve to put up with a dangerous, abusive, or hazardous work environment. A physician, or a clinic staff, only has so many “emotional marbles” for the day. One difficult patient with PD can sap all of the staff’s emotional strength. Most practices should severely limit how many moderate or severe patients with PD they treat.

Below is a discussion of the four more troubling PDs (paranoid, antisocial, borderline, and narcissistic) in the context of chronic pain, treatment, and associated risks to the clinic. There are other personality disorders that are essentially harmless, such as those with an avoidant personality. These patients are far less concerning for an outpatient pain clinic, and thus will not be discussed in this paper.

Comorbidity of Chronic Pain and Personality Disorders

Patients with comorbid PD and chronic pain present additional challenges. Personality traits color one’s perception of self and relationships. Maladaptive personality traits may affect how pain is perceived. Some studies have reported that up to 60% of patients with chronic pain meet criteria for comorbid PD and an estimated 30% of patients with chronic pain may have BPD.6–8 These prevalence rates support theories of predisposition of patients with PD to developing chronic pain syndromes.6 Patients who are being treated for their PD use less medication for pain relief than those who go untreated.7

Comorbidity of Migraine and Personality Disorders

A study analyzing the inpatient treatment of refractory chronic daily headaches found that 26% of hospitalized migraineurs also had a PD, particularly cluster B or cluster C.9 The presence of a PD was identified as a negative prognostic indicator, with these patients less likely to see moderate improvement upon discharge compared to non-PD patients.9 Cluster B PD comorbidity with migraine is associated with a more severe course of headaches, often with increased use of medications and poor treatment response.9–11 Over 62% of hospitalized migraineurs with a PD were found to be opioid dependent, compared to 37% of those without PD.9

Coexisting BPD with migraine is associated with higher rates of medication-overuse headache and increased frequency of unscheduled visits for acute migraine treatment.11 The treatment-resistant nature of migraines in BPD patients is likely driven by dysregulation of both affective and nociceptive systems. This population exhibits poor tolerance of internal pain. BPD patients exhibit decreased control over their emotions, which may magnify the pain-related functional distress.10 From a provider perspective, migraines in patients with BPD are often difficult to manage. Patients fare better when their PD is being addressed by mental health professionals.7

Treatment Approaches for PD Patients

Treatment for those with PD is difficult. PD patients often do not respect boundaries. If a physician chooses to treat a PD patient, limits must be set on physician contact – including telephone calls. It should also be made clear that abuse of staff is not tolerated. Referral to other health care providers, particularly mental health professionals, should be suggested in these patients.

Psychotherapists and psychiatrists who are experienced with treating PD are one key to successful treatment.  A collaborative approach also helps to protect the pain physician. Many PD patients do not do well with traditional, insight-oriented therapy treatment.  They respond better to a dialectical behavioral approach. For a therapy to be beneficial, it must be consistent and long-term. Depending on the level of insight the patient possesses, psychoeducation may also help.

Many physicians struggle to manage their countertransference in cases with PD. They often also become caught up in the anger, sadness, paranoia, or frustration exhibited by PD patients. These patients frequently present themselves in crisis with chaos and drama. It is important for the provider to not be caught up in the chaos and drama.  At times there are signs of a severe PD from the first visit or phone call to the clinic—with abuse, anger, major sense of entitlement, etc.  If the clinic is overrun by PD patients, or does not feel comfortable handling them, it may be best to refer and not become enmeshed in the relationship.

Medications can improve the aggression, impulsivity, self-mutilation, anxiety and depression components of personality disorders. While there are no specific medications indicated for those with PD, antidepressants, mood stabilizers, and antipsychotics show promise in relieving the severity of these symptoms. Additionally, these medications may also improve headache severity. Patients with PD and severe, chronic pain present additional challenges for treatment. Due to the high rates of refractory chronic pain, medication dependence, and overuse headaches in this group of patients, it is important to limit and closely monitor addicting medications such as benzodiazepines and opioids for signs of misuse.

It often takes several specialists to help a patient with a PD, just as it does to adequately treat those with severe pain. It is important to recruit others, such as mental health providers, physical therapists, biofeedback therapists, etc., to aid in the treatment.

Personality Disorder Risk Factors

There are risks inherent in caring for those with these disorders. BPD is known to be strongly associated with an increased risk of self-harm and suicide, and associations with suicide have also been found for patients with antisocial personality disorder.12 Suicide in those with BPD is increased as patients progress into their late 20’s and 30’s. by that time, family and friends have often abandoned the person, and the “malignant loneliness” is worsened. Patients with impulsive, insensitive personalities are more likely to carry out vindictive or even violent actions. This places physicians and staffs in an uncomfortable and dangerous position.13

BPD patients average three lifetime suicide attempts, and up to 10% of those patients will die by suicide.13 Impulsivity and unstable mood puts many BPD patients in a chronic state of suicidality, characterized by frequent, non-fatal suicide attempts following stressful life events.13 The suicidality leads to frequent emergency room visits and hospital admissions by this group of patients.13 Despite the overwhelming frequency of non-fatal attempts, there remains a high risk of completed suicide in this population. Unfortunately, risk algorithms are not accurate at predicting which BPD patients will die by suicide.13 General considerations associated with completed suicide include treatment nonadherence and/or poor response to psychiatric therapy. APD patients are also at a higher risk for suicide.12 NPD may generally be moderately protective against suicidality, but due to the hardheaded nature of NPD, the few that are suicidal may be more likely to succeed.14 Patients with NPD are at an additional  risk of completed suicide when they also exhibit comorbid aggression, hostility, or substance abuse.14,15

Certain types of patients with PD (paranoid, antisocial, borderline, and narcissistic) are more likely to resort to frivolous lawsuits and partake in litigious behavior. This tendency also manifests in other areas of a PD patient’s life, including their employment and personal relationships.16,17 Choosing to treat an extreme personality disorder patient opens doors to potential legal action. Providers must proceed with caution when opting to manage these cases. A PD patient may initially present themselves as a victim before rapidly taking on the role of persecutor. Many patients with PD flip between the triad of victim, persecutor, and savior.

Careful documentation is important.  The setting of boundaries is essential. Suicide in BPD is unpredictable and difficult to prevent.13 Despite what is commonly practiced, repetitively admitting BPD patients to the hospital after each suicide threat or attempt may actually lead to an increase in completed suicide. This happens within the first few days upon leaving the hospital. Most patients with PD should be referred to psychiatry and psychotherapy. 13  


  1. Maintaining strict boundaries is crucial.
  2. Do not become caught up in the chaos and drama.
  3. Limit the number of moderate or severe patients with PD in your practice.
  4. Refer to others for concurrent care, particularly mental health professionals.
  5. Be very careful, and greatly limit, controlled substances.
  6. Check the PMP for each visit.
  7. Do not tolerate any staff or provider abuse.
  8. If a patient “splits” on the provider, or levels severe anger, the approach of “killing them with kindness”, or reasoning and bargaining with the person, usually does not work. Do not hesitate to call the police in difficult situations.
  9. Be very conservative when recommending invasive procedures.
  10. Document everything.
  11. Consider taking a “dialectical” approach.
  12. Dismiss from your practice PD patients who cross lines or create havoc, or are dangerous to you or the staff. You do have to dismiss by following accepted guidelines, particularly being careful not to abandon the patient.
  13. Place limits on the patient calling you after hours.
  14. Place limits on emails and calls to your clinic.
  15. Remember, these patients create more of an emotional burden on a staff and provider. We only have only so many “emotional marbles” for our day or week. One difficult encounter may sap all of our marbles.


It is crucial to recognize those patients with borderline, narcissistic, antisocial, or paranoid personality disorder.  Patients with these types of personality disorders often suffer a poor outcome.  They require a multidisciplinary approach. Boundaries and limits must be enforced. It is important not to become caught up in the “chaos and drama” of the patient. Without recognition and adequate management, these patients place the pain provider at risk.


Olivia Lee is a fourth year medical student at Des Moines University. Her clinical interests include the interface of psychiatry and neurology. Lawrence Robbins is an assistant professor of neurology, Chicago Medical School. He is in private (neurology and headache) practice in Riverwoods, Illinois. Lawrence has contributed to 390 articles/abstracts and written 5 books (on headache). Address correspondence to Lawrence Robbins at


  1. Lenzenweger MF, Lane MC, Loranger AW, Kessler RC. DSM-IV Personality Disorders in the National Comorbidity Survey Replication. Vol 62.; 2007. doi:10.1016/j.biopsych.2006.09.019
  2. C W, A B, A T, et al. The prevalence of personality disorders in the community: a global systematic review and meta-analysis. Br J Psychiatry. 2020;216(2):69-78. doi:10.1192/BJP.2019.166
  3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington D.C: American Psychiatric Press; 2013.
  4. Helle AC, Watts AL, Trull TJ, Sher KJ. Alcohol Use Disorder and Antisocial and Borderline Personality Disorders. Vol 40.; 2019. doi:10.35946/arcr.v40.1.05
  5. Kacel EL, Ennis N, Pereira DB. Narcissistic Personality Disorder in Clinical Health Psychology Practice: Case Studies of Comorbid Psychological Distress and Life-Limiting Illness. Behav Med. 2017;43(3):156-164. doi:10.1080/08964289.2017.1301875
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  7. Sansone RA, Sansone LA. Chronic Pain Syndromes and Borderline Personality. Innov Clin Neurosci. 2012;9(1):10. /pmc/articles/PMC3280073/. Accessed August 7, 2021.
  8. KL D-G, DJ W, BK L, AL C. A Systematic Review of Personality Disorders and Health Outcomes. Can Psychol. 2015;56(2):168-190. doi:10.1037/CAP0000024
  9. Lake Iii AE, Saper JR, Hamel RL. Comprehensive Inpatient Treatment of Refractory Chronic Daily Headache. 2009. doi:10.1111/j.1526-4610.2009.01364.x
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  13. Paris J. Suicidality in borderline personality disorder. Med. 2019;55(6). doi:10.3390/medicina55060223
  14. L G, H B-F, M MP-R, et al. Personality disorders and health problems distinguish suicide attempters from completers in a direct comparison. J Affect Disord. 2013;151(2):474-483. doi:10.1016/J.JAD.2013.06.029
  15. Coleman D, Lawrence R, Parekh A, et al. Narcissistic Personality Disorder and suicidal behavior in mood disorders. J Psychiatr Res. 2017;85:24-28. doi:10.1016/j.jpsychires.2016.10.020
  16. Coffey CA, Brodsky SL, Sams DM. I’ll See You in Court…Again: Psychopathology and Hyperlitigious Litigants. J Am Acad Psychiatry Law Online. 2017;45(1).
  17. Michael Farnsworth, V. John Ella. The Legal Consequences of Hiring Narcissists. Published May 1, 2015. Accessed July 6, 2021.

Long Haul COVID-19

Olivia Lee and Lawrence Robbins, MD


Over 325 million doses of COVID-19 vaccines have been distributed in the United States, and much of the country is looking forward to a return to normalcy. For many, the widespread access to vaccines signaled the pandemic’s defeat, but for millions of COVID-19 survivors, the sequelae following acute infection will trouble them long after the country has returned to its normal state of affairs.

Recent studies have reported that up to 30% of COVID-19 patients experience persistent symptoms in the months following acute illness.1 Lingering myalgias, joint pains, headaches, shortness of breath, fatigue, dizziness, cardiac issues, and brain fog are just some of the reported symptoms.  These often continue long after the virus has been cleared from its host.2 Patients who experience lingering symptoms are collectively termed COVID-19 long-haulers, and diagnostic tests to quantify their disease status are being explored. Long haul COVID-19 has emerged as a growing challenge for physicians, who are working to identify effective treatment strategies for these chronic complications. This paper serves to briefly highlight diagnostic and therapeutic developments in the management of long haul COVID-19.

Demographics of Long Haul Covid Patients

Researchers have begun to establish a general profile of people with long hauling effects of COVID-19.. This may help identify those who are at the greatest risk for developing these chronic COVID-19 complications. Various studies have supported the notion that long haul COVID-19 disproportionately affects patients of older age, higher body mass index, female sex, or those with preexisting asthma.2,3 Female COVID-19 long-haulers are more likely than males to report anxiety, low mood, myalgia, fatigue, insomnia, and memory impairment.4

One study published in 2021 separated the most common symptoms into three “clusters” based on co-occurrence: Cluster A included myalgia and fatigue, Cluster B included low mood, anxiety, and sleep disturbance, and Cluster C included memory impairment, cognitive impairment, and attention deficit.4 Several reports indicate that the likelihood of experiencing these lingering symptoms may be independent from the severity of the acute COVID-19 infection. This suggests that the severity of the acute infection is not a reliable indicator of the risk for developing chronic complications.1,4

Diagnostic Measures

Currently there are no accepted diagnostic tests for long haul COVID-19.  Diagnosing this condition is dependent upon the patient’s history.5 Many COVID-19 long-haul symptoms are nonspecific and could be attributed to other conditions. Long haul COVID-19 is a diagnosis of exclusion. Alternative explanations for a patient’s nonspecific symptoms must first be considered.

Some studies have identified pro-inflammatory markers as being associated with long term COVID-19 illness. Increased levels of pro-inflammatory markers found in long haul patients include CRP, TNF-alpha, IL-1α, IL-1β, IL-6, IL-17A, IL-18, MCP-1, natriuretic peptides, ferritin, troponin, and D-dimer. 2,5,6 These biomarkers are nonspecific and present in other inflammatory conditions. The inflammatory markers have to be interpreted with caution. There are several papers that describe a paucity of pro-inflammatory markers in suspected cases of long haul COVID-19.2 The reasons for these inconsistencies is unknown and warrants further analysis. Despite this conflicting information, it may still be worthwhile to examine pro-inflammatory markers in suspected long haul COVID-19 patients.5 While these markers do not definitively diagnose long haul Covid-19, they provide supporting evidence.

Additionally, the biopsychosocial impact of COVID-19 long haul symptoms is an important consideration. Experiencing brain fog, fatigue, anxiety, depression, and other symptoms will generate more anxiety and depression.  The long haul syndrome sometimes resembles the post-traumatic syndromes observed following the Gulf War and 9/11.4 Thus, a psychological assessment may be indicated in evaluating cases of long haul COVID-19 to determine whether there are neuropsychiatric components that contribute.


Several medications are undergoing clinical trials for treating long haul COVID-19: C-C Chemokine Receptor Type 5, (CCR5) antagonists, antiparasitics, and monoclonal antibodies. Physicians at various treatment centers report repurposing medications (including maraviroc, ivermectin, and leronlimab) for treating COVID-19 long-haulers. They provide mixed accounts of the efficacy of these medications. Ivermectin,  an antiparasitic medication, has demonstrated promising results in treating long haul COVID-19.7,8 Its clinical benefits in long-haulers may be attributed to its modulating effects on the immune system. Ivermectin’s suppression of IL-6 may be a key to its benefit.7

Psychotherapy may be helpful in dealing with the devastating consequences of COVID-19. Other avenues such as multi-disciplinary rehabilitation have demonstrated success in subsets of COVID-19 long-haulers. These interventions include stretching, light aerobic activity, breathing exercises, physical therapy, and behavior modification.2 These multi-disciplinary approaches are able to tailor the treatment plan to the individual. There are a growing number of clinics specializing in evaluating and treating long haul patients. 

Vagus nerve stimulation, used for headaches, epilepsy, and depression, has recently been explored as a potential adjunctive therapy for long-haul COVID-19 9. There are reports of improvement in COVID-19 long-haulers undergoing non-invasive vagus nerve stimulation.10,11


Physicians are in the early stages of understanding how to effectively manage long haul COVID-19. Researchers have begun to characterize the profile of long-haulers. Clinical assessment currently depends primarily upon patient histories. Scientists and long haul COVID-19 treatment centers are conducting research into the immune status of long haulers. A vigorous autoimmune response seems to be the likely culprit for the majority of symptoms.  Several pharmaceutical interventions are undergoing clinical trials, but there are no definitive results at this point. Many of the current recommendations are targeted towards symptom management.  Over time recommendations for testing and therapy will emerge.

About the authors: Olivia Lee is a fourth year medical student at Des Moines University. Her clinical interests include the interface of psychiatry and neurology. Lawrence Robbins is an assistant professor of neurology, Chicago Medical School. He is in private (neurology and headache) practice in Riverwoods, Illinois. Lawrence has contributed to 380 articles/abstracts, and written 5 books (on headache). Address correspondence to Lawrence Robbins at


  1. Logue JK, Franko NM, McCulloch DJ, et al. Sequelae in Adults at 6 Months after COVID-19 Infection. JAMA Netw Open. 2021;4(2). doi:10.1001/jamanetworkopen.2021.0830
  2. Yong SJ. Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments. Infect Dis (London, England). 2021:1-18. doi:10.1080/23744235.2021.1924397
  3. Sudre CH, Murray B, Varsavsky T, et al. Attributes and predictors of long COVID. Nat Med. 2021;27(4):626-631. doi:10.1038/s41591-021-01292-y
  4. Sykes DL, Holdsworth L, Jawad N, Gunasekera P, Morice AH, Crooks MG. Post-COVID-19 Symptom Burden: What is Long-COVID and How Should We Manage It? Lung. 2021;199(2):113-119. doi:10.1007/s00408-021-00423-z
  5. Greenhalgh T, Knight M, A’Court C, Buxton M, Husain L. Management of post-acute covid-19 in primary care. BMJ. 2020;370. doi:10.1136/bmj.m3026
  6. Xiao N, Nie M, Pang H, et al. Integrated cytokine and metabolite analysis reveals immunometabolic reprogramming in COVID-19 patients with therapeutic implications. doi:10.1038/s41467-021-21907-9
  7. Zaidi AK, Dehgani-Mobaraki P. The mechanisms of action of Ivermectin against SARS-CoV-2: An evidence-based clinical review article. J Antibiot (Tokyo). June 2021:1-13. doi:10.1038/s41429-021-00430-5
  8. Aguirre-Chang G, Castillo Saavedra E, Yui Cerna M, Trujillo Figueredo A, Cordova Masias J. Post-Acute or Prolonged Covid-19 : Treatment With Ivermectin for Patients With Persistent , or Post-Acute Symptoms. ResearchGate. Published 2020. Accessed June 29, 2021.
  9. Azabou E, Bao G, Bounab R, Heming N, Annane D. Vagus Nerve Stimulation: A Potential Adjunct Therapy for COVID-19. Front Med. 2021;8:625836. doi:10.3389/fmed.2021.625836
  10. Silberstein S. Non-Invasive Vagus Nerve Stimulation May Treat Migraine in Patients with COVID-19, According to Neurologist Stephen D. Silberstein, M.D. | Business Wire. Published February 16, 2021. Accessed June 27, 2021.
  11. Lawson A. MUSC study to address post-COVID neurological and psychiatric symptoms using at-home format | MUSC | Charleston, SC. Published November 16, 2020. Accessed June 27, 2021.

President’s Message: Thoughts on Addressing Disparity in the Midst of the “Opioid Crisis”

Harry J. Gould, III, MD, PhD

Pain occurs in both acute and chronic forms. In its acute form, pain is a modality that is essential for survival and is the signal that most frequently brings people to the attention of the healthcare professional.  Many cases of simple acute pain are readily treated without difficulty by physicians, practitioners in paramedical fields, and in many instances, by the lay public. Unfortunately, all too frequently problems that present as simple complaints of acute pain are the result of more a significant problem that if not accurately diagnosed and effectively treated can become a chronic condition that destroys the fabric of existence, not only for the individuals suffering the pain, but for families, loved ones, and society as a whole. In spite of its prevalence, there is a general lack of recognition that unassessed or poorly managed pain in and of itself is a problem about which we should be concerned and because of its prevalence the problem is also accompanied by substantial disparity for patient access to adequately trained providers, early evaluation and proper treatment.

For proper pain control and rationale management, society relies heavily on trained physicians and healthcare professionals for guidance. Unfortunately, the number of patients needing relief from intractable pain far exceeds the number of healthcare providers who are adequately trained to meet that need. The management of complex pain problems, thus, all too frequently falls to those with limited training in assessment and treatment strategies and little familiarity with modalities used for pain control.

In the early part of this century, the predominant treatment offered for pain control was largely a pharmacologic modalities. Unfortunately, a significant portion of the pharmacologic options included agents used by a section of society for unintended reasons e.g., affecting changes in sensory and emotional perception and cognition for recreation, which led to inconsistent, often inadequate, management of pain for those in need and the current “opioid crisis.” Because of concern for legal reprisal and the recognition that the additional time required to comply with important monitoring regulations is not accompanied by a comparable increase in compensation, fewer practitioners have been willing to treat pain or they have shifted focus and limited the offered treatment modalities to more lucrative, unidimensional approaches, thereby further exacerbating the already significant disparity between practitioners and patients for access to comprehensive evaluation and care.  The problem is further exacerbated by social limitations related to direct cost of physician visits, necessary absences from employment responsibilities to make and keep appointments, potentially additional need for care of children and transportation to care. These limitations result in delays in obtaining expert assessment, in the timely implementation of appropriate treatment and the increased likelihood of establishing chronicity of the problem with its inherent increase in co-morbid health conditions, higher costs for prolonged treatment and the development of maladaptive behaviors associated with the recognition of secondary gains.

Oddly enough, the COVID-19 pandemic and its requisite need to adapt in order to provide “social distanced” care for patients, may have enabled more physicians and healthcare administrators to recognize a possible next step in the reduction of healthcare disparity in that that when appropriately applied, telemedicine platforms can be very effective in organizing and implementing routine care in their practice and provide more uniformity of care in the communities they serve. Clearly, in person visits will always be essential in patient care and remains the preferred option for many patients and physicians alike, but it is also recognized that the virtual-visit can provide a viable option when offered for practices where access to care is limited and widespread disparities prevail.

Practitioners have noted that with the virtual-visit platforms, patients seem to be more compliant with their follow-up visits. They have also found that the virtual-visit platforms can make it possible to more easily manage schedules in the event of patient tardiness or failure to show. The primary weakness of virtual platforms is the lack of a physical exam and a significant reduction in the practitioner’s ability to assess patient affect and body language, making it more difficult to recognize undisclosed problems that should be addressed. 

Patients also have found virtual-visits satisfying. Although many continue to prefer in person visits, many have noticed improved convenience and a significant reduction in associated costs related to needs to take time off from work (visits can be done on a break at the office), to arrange for daycare, to lost time related to traveling significant distances and dealing with heavier than accustomed to traffic often found in urban centers where the specialists tend to locate their practices. There is also less downtime spent in waiting rooms especially when times are greater than normal when the doctor is delayed or other patients have arrived late or have extra needs.    

From the specialist’s perspective, especially for specialists in pain medicine, a limitation to broader utilization of virtual technology to improve the patient to specialist ratio is that frequently referrals for specialist evaluation and recommendations are assumed, even for routine pain problems, to be a complete transfer of care accompanied by assumption of responsibility for the patient’s primary care, implementation of pain care and routine follow up. Because referrals for pain issues can come from virtually all medical specialties, this approach rapidly fills the specialist’s available appointment slots thus limiting the ability to accept new referrals because of the requisite need for maintaining routine follow-up visits to monitor response to care and patient compliance.

A more effective approach might be to gather a team of specialists that could work with primary providers to evaluate a patient, develop an appropriate treatment plan and in the process impart many of the basic skills of assessment and treatment thus empowering the physician to be able to care for his/her own patient. Potentially, the patient could be exposed to a broader range of treatment options, experience less long-term morbidity related to frequent and extended trials of an ineffective “hammer and nail” approach to care and would benefit from the earlier implementation and response to appropriate management options provided closer to home by a physician with whom they have developed a relationship. Because of the collaborative relationship that is established between the primary physician and the team of specialists, the patient would have access to a network of additional treatment resources, if needed, and the specialist would benefit from having more time to be available to collaborate with other primary providers and to work on more complicated, less routine, pain problems.

Coincidentally, just such a program, Project ECHO, has been developed, trialed and was successfully launched in 2003 at the University of New Mexico Health Sciences Center in Albuquerque. For those who are interested in learning more about Project ECHO and how it might help your practice while contributing to a reduction in the disparity of pain care for many in our community, we will have the good fortune to hear Joanna Katzman, M.D. speak on “Pain Management in 2021: Exploring the Benefits of ECHO Pain Telementoring and Direct Telehealth for Your Practice” at the upcoming annual meeting of the Southern Pain Society. The meeting will be held in person in New Orleans, from September 10-12, at the Astor Crowne Plaza. I encourage you to register for the meeting on our website,, and join me in the ‘Big Easy’ to hear more. I look forward to seeing you there.

Adverse Effects and Clinical Trials: The System is Broken

The CGRP Monoclonal Antibodies for Migraine Are a Prime Example

Lawrence Robbins, M.D.

This letter is in response to an excellent July, 2020 article “Migraine and CGRP Monoclonal Antibodies: A Review of Cardiovascular Side Effects and Safety Profile” (Boldig and Butala) in the International Journal of Neurology and Neurotherapy. (1) There are a plethora of adverse effects (AEs) from the CGRP monoclonals (mAbs) that were not identified in the Phase 3 trials. Unfortunately we frequently encounter this with new drugs. It often takes several years to identify an accurate picture of the adverse effect profile.

The package insert (PI) for the CGRP mAbs, as with many of the new drugs, identifies few AEs. The reasons for this include:  1. trial investigators did not use a checklist of AEs (a checklist is almost never utilized during drug trials) 2. as with most drug trials, the studies were powered for efficacy but would need many more patients to accurately assess AEs 3. the studies do not extend long enough in order to identify the true adverse effect profile and 4. adverse effects become “disaggregated”.  For instance, one person may say they have malaise while another may state they suffer from fatigue. This adverse effect is disaggregated and subsequently not included in the PI. After the study is completed these effects may be reaggregated, but that method is not accurate.

To accurately assess AEs post-approval, we must examine multiple lines of evidence. The FDA/FAERS website is an important source of information. Unfortunately, the side effects listed are adverse events, not necessarily adverse effects. As of January 2021, (2.5 years post-launch) there were 40,378 adverse events catalogued from the four CGRP mAbs.  On the FDA website, serious adverse events include those that are life threatening, or that resulted in hospitalization. 5,562 serious adverse events were listed. These numbers are staggering, particularly considering that the vast majority of adverse effects, even serious ones, go unreported.  Erenumab resulted in the bulk of the adverse events. This is most likely because erenumab was the first to market and has been the CGRP mAb most widely utilized. Save for constipation, I do not believe that erenumab is necessarily more likely to produce adverse effects than are the other 3 mAbs. 

After the launch of the drug, another line of evidence is the available post-approval studies and case reports.  One of the observational studies concluded that adverse effects resulted in 33% of erenumab discontinuations (2). Another study described 63.3% of patients as having reported an adverse effect, but they concluded that the CGRP monoclonal antibodies were well tolerated. (3)

We published a study of 119 chronic migraine patients who had utilized one of the CGRP monoclonals. (4) We incorporated a checklist of 19 possible adverse effects. The patients were initially asked about adverse effects by posing the question, “Have you experienced any issues, problems, or side effects from the injection?” Subsequently the patients were interviewed regarding each possible adverse effect, utilizing the checklist. A determination was made, between the patient and researcher, as to whether the adverse effect was truly due to the use of the monoclonal. 66% of the patients identified at least one additional adverse effect via the use of a carefully chosen checklist. 18 patients had one additional adverse effect. 56 patients identified 2 to 8 additional adverse effects.

An additional line of evidence is the opinion of high prescribers of the drug. This is gleaned from chat boards of headache providers, private correspondence, and discussions during conferences. Some headache providers feel that the CGRP monoclonals are safe and adverse effects are infrequently encountered. Others believe, as I do, that the mAbs result in a number of deleterious effects.  There is no consensus at this time.

In addition to headache provider comments, the CGRP patient chat boards provide valuable insight into adverse effects. We assessed 2,800 patient comments regarding adverse effects. We judged 490 to be highly believable. The list of common adverse effects, as identified by the highly believable comments, aligns well with our other lines of evidence.

 After assessing the various post-approval lines of evidence, there are signals that the following adverse effects may result from the use of CGRP monoclonals: constipation, anxiety, injection site reactions, weight gain or loss, worsening hypertension, increased headache, insomnia, depression, hair loss, joint pain, fatigue, irritability, muscle pain or cramps, nausea, rash, sexual dysfunction, and tachycardia (or other heart irregularities).  Most likely there are others as well.  In addition, there have been cases of reversible cerebral vasoconstriction syndrome and stroke. Angina and myocardial infarction have also been reported. Thomas Moore, a leading expert in the acquisition of adverse effects of drugs, published a review of the CGRP monoclonals in the online journal QuarterWatch. QuarterWatch utilizes various resources, including FDA reports and published post-approval studies. (5) The report cites the “sheer number of case reports,” and concludes that “…it is likely that adverse effects of this migraine preventive were underestimated in the clinical trials.”

This discussion has revolved around short-term adverse effects. Long-term effects, which are unknown at this time, remain a serious concern. CGRP has been important in various species for 400 million years. We ignore evolution at our peril. There are a multitude of beneficial effects partially mediated by CGRP. These include protecting our cardiac and cerebrovascular systems through vasodilatory effects(particularly during stressful conditions), resisting the onset of hypertension, decreasing oxidative stress in the aorta, improving circulation in the face of heart disease (including heart failure), aiding with wound healing, burns, and tissue repair, minimizing the effects of sepsis, aiding in the healing of GI ulcers, protecting the GI mucosa, affecting GI motility, contributing to flushing and thermoregulation, aiding with cold hypersensitivity, regulating bone metabolism, protecting the kidneys in certain pathologic conditions, playing a role in regulating insulin release, affecting metabolism and body weight, and helping to mediate the adrenal glucocorticoid response to acute stress in the mature fetus. (6) The hypothalamic-pituitary-adrenal axis may be affected by CGRP, and this has not been adequately studied. If these mAbs are to be used in adolescents, we must first study the hormonal effects.

 The package inserts often do not reflect the reality of the AE profile. I believe that the FDA should overhaul the guidelines as to how adverse events are acquired in formal studies. This situation has been harmful to patients. This is not unique to the mAbs. We should work towards improving the early identification of an accurate adverse effect profile. Certain adverse effects, such as sexual adverse effects, or depression, are missed in formal studies.

The CGRP monoclonal antibodies have been beneficial for many migraineurs. The efficacy of these mAbs rivals that of onabotulinumtoxinA. However, CGRP plays a crucial role in many physiological processes. There is evidence for a multitude of deleterious effects that result from blocking CGRP. Long-term effects are completely unknown. We should be cautious and judicious in our use of the CGRP monoclonal antibodies.

Disclosure: L. Robbins is a speaker for Abbott Labs, Teva, and Amgen.




  1. Boldis K, Butala, N (2020) Migraine and CGRP Monoclonal Antibodies: A Review of Cardiovascular Side Effects and Safety Profile. International Journal of Neurology and Neurotherapy 7:101: DOI:10.23937/2378-3001/1410101
  2. Robblee J, Devick K, et al. (2020) Real-World Patient Experience with Erenumab for the Preventive Treatment of Migraine.  Headache 60:9, p. 2014-2025.
  3. Alex A, Vaugh C., Rayhill M (2020) Safety and Tolerability of 3 CGRP Monoclonal Antibodies in Practice: A Retrospective Cohort Study. Headache 60:10, p. 2454-2462.
  4. Robbins L, Phenicie B, (2020) CGRP Monoclonal Antibodies for Chronic Migraine Prevention: Evaluation of Adverse Effects Using a Checklist. Practical Pain Management 20:2, p. 48-52.  (online at, March/April, 2020)
  5. Moore T. (2019) Aimovig, Ajovy, and Emgality. QuarterWatch Reports 24:16, p. 2-4.
  6. Robbins L (2018) CGRP Antagonists: Physiologic Effects and Serious Side Effects (Letter). Headache 58:9, p. 1469-1471.

Laser Treatment Offers a 5 day Treatment for COVID19

Bert Ray, MD

Laser therapy has been utilized for multiple medical problems, as the light energy improves mitochondrial function in cells that are involved with medical illnesses, has an anti-inflammatory effect, boosts the immune response, and restores oxidative redox balance. Thus, the laser energy helps rebalance the oxidative redox system that underlies the inflammation involved in almost all current medical issues, including cardiovascular diseases, diabetes mellitus, Parkinson’s, dementia, chronic pain, and even cancer.

Photodynamic therapy consists of utilizing a “photo-sensitizer”, of which there are many, and they will vary depending on the wavelength of laser light to be used. For example, methylene blue or curcumin can be used to “sensitize” target tissue for red and infrared laser wavelengths. The sensitizer draws the light energy to the intended source and thus, the combination of the laser energy and the photosensitizer amount to what is known as photodynamic therapy.

At our clinic, we use a Weber Medical laser which can utilize red, infrared, yellow, blue, green, and ultraviolet light wavelengths. It is also the only laser that we have found that can allow for dermal, intra-articular, and intravenous applications. We have found this treatment to be extremely helpful in doing either trigger point injections or regenerative injections, because we can use laser light through the needle and place it directly at the site of injection, thus giving us a synergistic effect on the applied treatment.

COVID19 has presented an opportunity to evaluate the effects of photodynamic therapy on the coronavirus. We know from previous work that methylene blue intra-nasal and intra-orally combined with red and infrared laser can kill viruses and bacteria in the oral cavities. In the unique study attached to this note, photodynamic therapy was tested against COVID 19 in patients who tested positive and were in Stage 1 or 2 symptomatically, utilizing riboflavin as the photosensitizer and blue and ultraviolet wavelengths. The results showed excellent improvement in 5 days, indicating that here is an effective, non-invasive treatment for COVID 19. Further studies are now ongoing to test this treatment for hospitalized COVID 19 patients, and also to see if this non-invasive treatment can prevent COVID 19.

Please review this recently published article on a new and effective treatment available for non-hospitalized COVID Stage 1 or 2 patients. Keep in mind that even though these patients didn’t require hospitalized care, they were all very sick people, who made rapid recovery. The implication of a rapid recovery indicate that a shorter quarantine time could allow people to resume normal function in a shorter time, creating less drain on the economy, both directly by avoiding hospitalizations and indirectly by early return to work, home functions, schools, etc.

I would refer our readers to Google ISLA (Intl Soc for Medical Laser Application) for further articles on photodynamic therapies.

In addition, Weber Medical now has kits available for HOME treatment using  the same protocol as in their published study.  The whole family can use these kits if anyone gets COVID.  You  don’t have to go to a doctor for this treatment. 


Reduction of the Viral Load by Non-Invasive Photodynamic Therapy in Early
Stages of COVID-19 infection. Am J of Viro and Dis. 2020; 2(1): 01-05

Successful Reduction of SARS-CoV-2Viral Load by Photodynamic Therapy (PDT) Verified by QPCR – A Novel Approach in Treating Patients in Early Infection Stages

Chaos, Migraine, and Evolution

Lawrence Robbins, MD


Migraine often results in disability and diminished quality of life. Despite this, our species remains particularly vulnerable to migraine. Why is this so?  Evolution may provide answers. The study of evolution and disease is not simply an academic exercise. In studying the history of our species, and those that preceded us, we may be able to develop safer and more effective treatments. We ignore evolution at our peril.

Chaos theory is a subset of nonlinear dynamics. Nature has been able to utilize chaotic dynamics in the brain, heart, and elsewhere (Korn, & Faure, 2003). Chaotic dynamics provide advantages over stochastic (random) or reductive (simple, linear) systems. Neurons and neuron clusters effectively utilize chaos. One hallmark of chaos is the extreme sensitivity to initial conditions (Bird, 2003). This leads to the classic butterfly effect, where a tiny perturbation in the beginning results in enormous changes down the line. Initial conditions played a significant role in the development of Homo sapiens (Bird, 2003). If we travelled back in time, and changed even the tiniest initial traits, today’s human would appear significantly different. 

Chaotic dynamics may play several roles in migraine pathophysiology. For instance, a tiny initial change in blood flow, such as occurs due to a patent foramen ovale (PFO), could eventually lead to the initiation of a migraine. The complex electrical wiring of the brain involves chaotic dynamics (Korn et al., 2003).  Chaos, migraine, and evolution are intimately interwoven. This paper outlines some of their connections. 


Chaos is a math-based subset of non-linear dynamics. Chaos improves the adaptability, efficiency, and versatility of neuronal systems.  A number of biological systems are governed somewhat by chaotic dynamics.  These systems include the ion flow and electrical activity of the brain, the beating of the heart, blood glucose levels, and glycolysis. Several studies have demonstrated chaos at the cellular level in the brain (Schweighofer, Doya, et al., 2004). By evaluating the flow of ions through the energy barriers of the channel protein, maps reveal the chaotic controls. Algorithms and numerical solutions have been constructed revealing when the transition to chaotic dynamics occurs (Landau, Sompolinsky, 2018). Characteristics of chaotic systems include, most importantly, an exquisite sensitivity to initial conditions.  Chaos is deterministic and predictable solely from one point to the next, but not beyond that point. The initial conditions are then reset after each point.

When compared to reductive or stochastic systems, chaotic systems save energy and are more adaptable.  Chaotic dynamics are involved in governing cortical spreading depression (CSD) (Pietrobon, Moskowitz, 2014). Chaos has been demonstrated to play a role in K+, Ca+, and Na+ movements. The flow of ions about the cell has been determined to be a combination of randomness, reductive(linear) movements, and chaotic processes. A small initial change in K+ efflux, or Ca+ influx, will result in a large effect downstream. Clusters of neurons, as well as single neurons, fire in a variety of patterns. These range from regular oscillating patterns to bursts, and everything in between. Neuronal systems undergo transitions that carry them between diverse states (Vreeswijk, Sompolinsky, 1998). Chaotic dynamics partially govern both individual neurons, as well as groups of neurons.


Tiny CNS perturbations may be brought about by the usual migraine triggers such as weather, stress, or hormonal changes. Through chaotic dynamics this may result in plasma protein extravasation (PPE) and cortical spreading depression, both of which are vital processes in the pathophysiology of migraine (Kernick, 2005). Medications affecting CSD may influence the neuronal membrane through chaotic controls. A small number of patients with patent foramen ovale (PFO) have experienced resolution of their migraines after PFO closure. The usual explanation for the PFO induction of migraine is via microemboli. It is also possible that chaotic dynamics play a role.  A small change in blood flow downstream (the heart) may induce a significant change in CNS dynamics upstream.

Chronic migraine pathophysiology involves wind-up and central sensitization(CS) . These are possibly controlled by chaotic dynamics. Thalamic recruitment involved in expansion of the pain area is likely governed by chaotic dynamics. Thalamic-cortical circuits involve chaotic dynamics. The pathological shift of homeostasis observed in chronic CS, with a loss of brainstem inhibition, may actually reflect a loss of chaotic control (Vreeswijk,et al.,1998). This is similar to the loss of control in the heart, resulting in arrhythmia.  The brainstem periaqueductal grey (PAG)—important in migraine—has been shown to be under chaotic control thru P/Q- type Ca+ channels. Migraine physiology incorporates a combination of genetic and environmental factors.  Trigger factors that affect migraine include stress, weather, and hormonal   changes.   These may affect the delicate balance between interneuronal nonlinear, reductive, and stochastic dynamics.  This may lead to chronic migraine. When a system is forced or stressed, nonlinear dynamics may be affected. 

New onset daily persistent headache (NDPH) may result from a perturbation of neuronal dynamics. Emotional, infectious, or other stresses may influence the delicate balance between nonlinear dynamics and stochastic or reductive dynamics. This could lead to chronic head pain.

Calcium and sodium efflux occur with CSD. Potassium and P/Q calcium channels are also involved. This complex system is unlikely to be governed primarily by random or linear kinetics. Chaotic controls have been demonstrated to be involved with these ionic movements (Pietrobon, et al., 2014). Chaotic dynamics could explain some of the properties of CSD. The initiation of CSD may be brought about by a miniscule change in potassium levels. This tiny effect may activate receptors and result in a large change downstream. The result is CSD and oligemia. With the potassium efflux partially under chaotic control, the chaos probably helps to regulate the increased cortical hyperactivity inherent in the brain of some migraineurs.

The trigeminal nucleus caudalis, vital in migraine pathophysiology, may be activated by a tiny initial stimulus. Through chaotic dynamics, this may result in the release of pro-inflammatory peptides and a release of glutamate. CSD leads to increased plasma protein extravasation. Only chaotic dynamics may explain how this may be possible. The medications that affect CSD (amitriptyline, topiramate, sodium valproate) may influence chaotic dynamics via membrane effects. When nonlinear dynamics are involved, it possibly takes less drug to produce an effect. The periaqueductal gray matter is involved in a number of CNS processes, including migraine. There is evidence that the periaqueductal gray is partially controlled by chaotic dynamics (Schweighofer, et al., 2004).

The loss of chaotic dynamics may lead to a pathological shift of homeostasis. The loss of brainstem inhibitory activity may actually reflect a lessening of chaotic control, eventually leading to a migraine. Similar loss of chaotic dynamics may explain certain arrhythmias and epileptic seizures.

The primary excitatory neurotransmitter in the brain is glutamate.  Along with calcium, glutamate is crucial in the feedback process. Glutamate is directly involved in bi-directional communications between neurons and astrocytes. It is likely that glutamate feedback processes are critical in the generation of complex bursting oscillations in astrocytes. These glutamate-mediated events are involved in migraine, epilepsy, and memory storage. The control of this feedback process may be partially enacted through chaotic dynamics. The cascade of magnesium binding to N-methyl-D-aspartate (NMDA) in the periphery about the brain, with subsequent calcium influx, is very sensitive to minute initial changes (Kernick, 2005).  This cascade is important in peripheral sensitization, which leads to migraine attacks. These magnesium and NMDA effects may be under chaotic control.

Brain-derived neurotrophic factor (BDNF) is a neurotropin that modulates neuronal membrane excitability. BDNF was used in one study to affect hippocampal neurons (Fujisawa, Yamada, Nishiyama, Ikegaya, 2004). Chaotic dynamics partially govern patterns of electrical activity in hippocampal neurons. The hippocampal electrical system is a deterministic one with a few degrees of freedom. Neuronal chaos may be sensitive to change by the application of small amounts of materials, such as BDNF, that influence temporal spiking. The application of BDNF to cultured hippocampal neurons enhanced spike timing and resulted in stereotyped firing patterns. It was felt that BDNF influenced chaos through effects on membrane levels of sodium (Fujisawa, et al., 2004).  BDNF enhanced membrane conductance and thus stabilized the membrane. The application of BDNF affected the switching between periodic and aperiodic neuronal oscillations. BDNF has been linked to modulation of neuroplasticity. The BDNF application decreased irregularity of firing patterns by modulating neuronal outputs as well as inputs. The result was a BDNF-induced chaos stabilization. This was the first experiment to demonstrate a pharmacological stabilization of chaos at the neuronal level (Fujisawa, et al., 2004).


Chaos and evolution are intimately interconnected. There is a chaotic (non-linear) connection between phenotype and genotype. This complex relationship is constantly in flux. A single mutation may be inconsequential, or it may result in enormous changes that are unpredictable. This is typical for a non-linear system. With these unpredictable mutations, iterations over thousands of generations will usually result in evolutionary changes (McKee, 2000). It is debatable as to how much the environment plays a role, versus genetic changes that are generated internally.

The unpredictability of evolution is typical of non-linear systems. Most discussions of evolution predictors focus on random, stochastic processes (mutations, genetic drift, random environmental changes). A reductive system would behave in a much more orderly, predictable manner. However, these fixed reductive systems are limited, and non-linear dynamics allows for enhanced evolutionary adaptability. The behavior of evolutionary systems is extremely sensitive to initial conditions. This was demonstrated during the quaternary period. At the beginning of each interglacial, the initial circumstances determined the outcome of that period. Between interglacials there were differences that were unpredictable, due to the non-linear nature of the system (Bird, 2003).

Non-linear dynamics lead to a system that is not scaled. The tree of life is fractal, and follows non-linear dynamics. The branches of the tree are continuously being split, resulting in evolutionary changes.  If we travelled back 5 million years, and re-started the human evolutionary process, the result would be dramatically different. This is the nature of a non-linear system. A simpler stochastic reductive system would be predictable but limited. It has been demonstrated that, when many traits interact, chaotic dynamics may govern phenotypic evolution.   Ancient species in human evolution, such as Australopithecus and Homo habilis, may have diverged due to chaotic dynamics (McCann, Yodzis, 1994).

Natural selection utilizes chaotic dynamics, chance, and coincidence (McKee, 2000). Natural selection does not invent, it tends to mosey along and tinker. The chance mutation must be coincidentally beneficial because of some environmental change.  For instance, if our ancestors needed robust teeth due to changing climactic conditions, those who happened to have larger teeth would have prevailed. Chaotic dynamics oversees chance and coincidence in the evolutionary process.


 Examining evolutionary systems in relation to disease is much more than an academic exercise. The evolutionary history will give us a complete picture of a disease. Understanding the evolutionary foundation may help us in developing safe and effective treatments.

Illness can be considered through two frameworks: 1. a proximate view, and 2. an evolutionary lens. The proximate view considers the nuts and bolts of a disease: pathophysiology, treatment, biochemistry, etc. It’s vitally important to also consider the disease process using an evolutionary viewpoint (Perlman, 2013). One essential question is: “why have migraines persisted, and why are humans still so susceptible to migraine?” The proximate lens says that migraine is a physical trait that involves multiple physiologic systems. The evolutionary framework begs the question: “why does our DNA code for migraine?”

There are physiological trade-offs that permeate evolution. While sickle cell disease is devastating, the sickle cell gene does also protect against malaria. Cystic fibrosis also involves serious trade-offs. Heterozygotes for cystic fibrosis were less likely to suffer dehydration from illnesses such as cholera. Genes exist to propagate themselves, sometimes to the detriment of the organism (the “selfish gene”)(Dawkins, 2013). This is also the story of migraine. Evolutionary benefits from migraine are possible (Loder, 2002).  It is also possible that our species simply continues to be vulnerable to migraine, and the evolutionary benefits are few. There are multiple genes involved in migraine, and evolution does not easily remove “bad genes”(Loder, 2002).

 It’s likely that migraines in humans increased as a result of our migration to more northern latitudes (Vigano, Manica, Di Piero, Leonardi, 2019).  Low vitamin D levels may help explain the increase in prevalence of migraine farther north (Prakash, 2010). The TRPM8 gene involves a receptor that plays a part in cold sensation and thermoregulation. TRPM8 (the “T” variation) is also linked to an increased risk for migraine (Dussor, Cao, 2016).  People who carry the “T” variation are better adapted to cold environments, and this adaptation likely improved their survival and reproductive success. Migraine may have been a negative consequence from this cold adaptation: another trade-off. The TRPM8 and latitudinal studies were the first to link migraine, evolution, natural selection, and geography (Vigano, et al., 2019).

The reasons why migraine persists are varied. While there is no epidemiological data from past millenia, the prevalence of migraine may be increasing. An increased sensitivity to light, smells, and sound could be beneficial under certain conditions. Migraine may be advantageous in combating certain infections (Loder, 2002). This may occur through an enhanced immune response, or by an increase in blood flow. Only a small percentage of people never experience headache (7% of men, and 1% of women), signaling that there may be some evolutionary advantage of headache.

Certain genes that result in harmless “quirks” in one environment can have deadly outcomes in other venues. Our modern environment certainly contributes to migraine frequency. The environment has radically changed, after millions of years of evolution (Cochran, Harpending, 2009).  For the vast majority of human history, we were primarily hunting and gathering. Recently, only 10 to 12 thousand years ago, societies in Southwest Asia (the fertile crescent) began to cultivate plants and domesticate animals. Many factors may contribute to increased migraine frequency: changes in culture, living circumstances, agriculture and diet, environmental toxins, densely packed populations, infections (particularly viral), harsh indoor lighting, loud speakers, poor sleep, and increased stress (Loder, 2002).  When modern hunter-gatherer societies switch to our “western diet,” they suffer from heart disease and an increase in cancer (Milton, 2000).  One of many examples where a changing environment has an impact on disease involves the genes for heart disease. These genes may not have been particularly detrimental for Stone Age humans, due to short lifespans. But as lifespans have been significantly lengthened, these genes have become threatening. Phenotypic and adaptive plasticity are significant factors in humans adapting to the changing environment (Perlman, 2013).

While migraine is three times more common in women than in men, the evolutionary explanation for this is unclear. Men generally did most of the hunting and gathering, for which migraine could pose disadvantages. For child care, food preparation, and homekeeping, migraine may possibly offer small evolutionary advantages. Migraine commonly decreases during pregnancy, providing an evolutionary incentive for more pregnancies.

It’s likely that migraine only afflicts the human species. Our ancient human brainstem has obstacles in coping with a cortex that is recently enlarged. With excessive afferent input, our brainstem may be overwhelmed. Having higher cortical functions not found in other primates may contribute to our continued vulnerability to migraine.   

Migraine may function as a defense mechanism against excessive stress, noise, or light (Loder, 2002).  The elevated sense of smell may serve as a defense from toxins or viruses entering the CNS. Vomiting may help to remove toxins. Women migraineurs probably have a lower prevalence of type 2 diabetes, compared to those without migraine (Fagherazzi, El Fatouhi, Fournier, et al., 2019).  An activation of the trigeminal nuclear complex could be protective (Loder, 2002).  If migraine offers protections for an individual, then that individual’s genes may be propagated more successfully. If an ancestral human experienced 100 migraines during a year, and just one of those migraines protected the person from harm, the trade-off would have been worthwhile. In an evolutionary framework, the cost of migraine may be inexpensive.

There is a difference between a defense and a defect. Coughing is a defense, but becoming blue from hypoxia is not. We want to retain our natural defenses. The calcitonin gene-related peptide (CGRP) associated with migraine may be advantageous under stress (Kee, 2018). CGRP has existed in a variety of species for hundreds of millions of years. CGRP plays various roles in the body, some positive, some harmful (Kee, Kodji, Brain, 2018). Under stress, CGRP is beneficial for our cerebrovascular and cardiovascular systems. Disrupting this natural defense, as happens with our CGRP monoclonal antibodies that prevent migraine, may be harmful.  The CGRP story is one example of the danger in ignoring the evolutionary importance of a compound.       

Natural selection is dependent on reproduction. After the reproductive years, a particular trait could very well become detrimental, but that does not affect gene propagation. In order to understand a trait (or disease) such as migraine, we must consider all of the evolutionary processes. These include genetic drift, mutations, migration, non-random mating, and natural selection (Perlman, 2013). Sometimes, natural selection produces opposing effects, resulting in a heightened vulnerability to disease.

 It’s imperative to not only view individuals through an evolutionary lens, but to also consider the phylogeny of the species (Perlman, 2013). The relationships between humans have morphed in the past 12,000 years (Cochran, et al., 2009).  One primary factor driving phylogenetic changes is the increase in population density, resulting in most humans living in significantly smaller spaces. Culture, which influences our state of disease or health, may also contribute to an increase in headache prevalence.

Headache and pain are adaptive responses. Being still, or in bed, may help repair damaged tissues. Incomplete or inadequate natural selection is often cited as the cause for our flaws or disease, but it is more likely that many illnesses are the result of compromises and/or design flaws (Nesse, Williams, 2012).  For example, our esophagus crosses our trachea. Because of this, our airway must inconveniently be closed every time that we swallow, to prevent choking. Allergies, atherosclerosis, nearsightedness, and nausea in pregnancy are similar examples stemming from evolutionary compromises and design flaws (Nesse, 2005, 2012).

Another important evolutionary concept to consider is intrinsic vulnerability (Nesse, 2011). Different species have various levels of vulnerability to certain diseases. Humans mature rather slowly, with infrequent reproduction. This is a factor regarding enhanced vulnerability of our species to certain diseases. It’s difficult for us to rid ourselves of genes that cause harm. Migraine involves a multitude of factors and genes, and it’s not likely that natural selection would be capable of eliminating migraine.

To more wholly understand migraine, we should venture beyond the proximate and physiologic processes. The evolutionary foundations of migraine are vitally important to study. Examining migraine under an evolutionary lens may help us in evaluating the safety of new treatments, such as the CGRP monoclonal antibodies. We must pay attention to evolution.


Chaos, migraine, and evolution are intertwined. Chaotic dynamics are vital within the central nervous system. Chaos is important at the ionic, neuronal, and neuronal cluster levels. Chaos may be involved in the generation of CSD. Sensitization and wind-up, crucial components of migraine, probably incorporate chaotic dynamics.

Evolution and natural selection involve chaos, chance, and coincidence. The evolutionary result of thousands of generations depends exquisitely upon initial conditions, characteristic of chaotic dynamics.

For myriad reasons, our species remains remarkably vulnerable to migraine. To understand migraine, we have to look farther than simple physiologic and proximate processes. We cannot truly understand migraine without examining the evolutionary underpinnings. The safety of new migraine treatments should be evaluated under an evolutionary lens.


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Update on Gepants: New Abortives for Migraine

Lawrence Robbins,M.D.

Gepants are small molecule calcitonin gene-related peptide (CGRP) receptor antagonists. The preventive CGRP monoclonal antibodies(Aimovig, Emgality, Ajovy) are large molecules, delivered once per month as a SQ injection. Seven gepants have been developed since 2004. (1) Telcagepant was extensively studied, but withdrawn due to hepatotoxicity concerns. CGRP has many effects throughout the body. CGRP triggers a cascade of inflammatory mediators that feed into the trigeminovascular system. By blocking CGRP, the gepants stop the process prior to inflammation.

Regarding migraine, CGRP is an inflammatory compound. They will initially be utilized as migraine abortives, but eventually they will also be used to prevent migraine. The gepants may be helpful for 3 groups of migraineurs. They will be prescribed for a number of patients who found triptans (sumatriptan, rizatriptan, zolmitriptan, etc.) to be ineffective. In addition, gepants will be used for certain patients who cannot tolerate triptans. Finally, for those patients with significant cardiac or cerebrovascular risk factors, the gepants may be relatively safe, since they do not constrict cardiac or cranial arteries. While efficacy is modest, these are well tolerated medications.

The first gepant to come to market will be ubrogepant. Almost 2,700 patients participated in the ubrogepant ACHIEVE studies. (2,3) The doses have ranged from 25mg to 100mg. The t-max is 0.7 to 1.5 hours. Approximately 20% of patients who used the 50mg dose were pain free after 2 hours. While 25mg and 100mg tablets of ubrogepant were evaluated, it is likely that 50mg will be the primary dose. Ubrogepant was well tolerated, with 2% to 5% of patients reporting nausea, somnolence, dry mouth, dizziness, or upper respiratory tract infections. No serious adverse events were reported. The safety and tolerability were also explored in a 52 week extension study. Few adverse events, and no hepatotoxicity was reported. The effect of ubrogepant on the patient’s most bothersome migraine symptom was evaluated 2 hours post-dose. 39% of those treated with ubrogepant reported that their worst migraine symptom was resolved. The therapeutic gain for ubrogegepant (active drug vs. placebo) is relatively low, 6.4%-9.4%. In comparison, the therapeutic gain for sumatriptan is 16%-21%.

Rimegepant is another gepant, in development for abortive and preventive use. The dose is 75mg, with a t-max of 2 hours. In the 2 main trials, 19.4% of patients achieved pain freedom at 2 hours. (4) 37% of patients reported freedom from their most bothersome symptom. As with ubrogepant, no significant liver toxicity was reported. Adverse events were low, with nausea being reported by 1.4% of patients. The therapeutic gain for rimegepant is 5% to 7.6%.

A third gepant, atogepant, is currently being studied.

The gepants will be a useful alternative to triptans. Many patients find triptans to be ineffective. Some migraineurs cannot tolerate the adverse effects of the triptans. For certain patients with cardiovascular risk factors, triptans may not be completely safe. Gepants will be considered in these clinical settings. The initial (2 hour) efficacy rates are fairly low, but it appears that gepants may become more effective over 2 to 8 hours. During the trials, these were fairly well tolerated medications. It will take at least several years before we are able to accurately assess the true adverse effect profile of the gepants.


1. Olesen J, Diener H-C, Husstedt IW et al Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. 2004. N Eng J Med 350:1104-1110.

2. Allergan Announces Positive Top Line Phase 3 Clinical Trial for Ubrogepant- an Oral CGRP Receptor Antagonist for the Acute Treatment of Migraine. Available at

3. Allergan Announces Second Positive Phase 3 Clinical Trial for Ubrogepant- an Oral CGRP Receptor Antagonist for the Acute Treatment of Migraine. Available at

4. Biohaven Announces Successful Achievement of Both Co-Primary regulatory Endpoints in Two Pivotal Phase 3 Trials of Rimegepant an Oral CGRP Receptor Antagonist for the Acute Treatment of Migraine Available at