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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.

YouTube

  • 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: A Fresh Approach to Pain Education

Harry J. Gould, III MD, PhD

During the past 30 years, we have observed the prescribing habits of physicians swing from a position of avoidance of opioid medications in the late 80’s and early 90’s to a position of liberal and virtually indiscriminate prescribing of opioids in the first decade of this century.  This trend paralleled a similar rise in overdose deaths associated with prescription opioids that led to the development of Washington State’s Multiagency Guidelines for Prescribing Controlled Substances with the goal to improve the safety and effectiveness of opioid treatment for chronic non-cancer pain.  Concern about the over prescribing and overdose deaths motivated the Institute of Medicine’s investigation of pain in America, the Centers for Disease Control’s declaration that the “Opioid Epidemic”, was considered the greatest healthcare crisis in U.S. history and the release in 2016 of their Guideline for Prescribing Opioids for Chronic Pain.

The broad understanding and agreement that the problem exists coupled with a desire for a rapid solution led to varied interpretations of prescribing guidelines.  Imposed policies and benchmarks for treatment standards often exceeded the intended goals of the drafters of the guidelines.  Physicians’ fear of criminal sanctions and strict disciplinary consequences associated with failure to comply with guideline standards led to a dramatic decline in prescriptions issued for opioid medications.  Unfortunately, the rapid reversal of the pendulum related to opioid medications, while significantly reducing the availability of prescription opioid medications has not produced a parallel reduction in opioid-related overdose deaths and the pendulum representing improvement in patient care seems to have remained steady throughout this period of healthcare volatility. How can we move closer to our goal of providing appropriate and adequate care for our patients in pain and mitigate the problem of the untoward adverse effects of opioid medications on patients and on society as a whole? 

“Across health care and society alike, there are major gaps in knowledge about pain” was one of the important conclusions drawn from the Institute of Medicine’s investigation of the state of pain care in America.  This is an important focus, but moving the mark toward improved patient care takes time and a concerted effort from a vast number of healthcare providers who view the problem from varied perspectives and training, from administrators and regulators of practice standards and from the patients we are hoping to serve. Incumbent on the approach to developing strong, patient focused principles for pain management is understanding that there are many tools that are effective for treating pain, but not all tools are necessarily appropriate or effective for treating every pain problem.  Each patient should be properly evaluated and should be involved in setting reasonable goals and making decisions in their care.  The appropriate tool or tools for the problem and the rationale for implementation should be carefully selected and administered when optimum.      

To this point, a new program to address the problem of provider and patient education has begun a trial run at the Louisiana State University Health Sciences Center in New Orleans.  The program is a longitudinal study targeting physicians in training in various specialties.  The program is administered to residents-in-training across the entire spectrum of their training and focuses on pain as it applies to their specialty. It measures levels of understanding of pain, its evaluation and management at each level of training and as they progress through their program toward certification. The initial trial runs focused on residents in obstetrics and gynecology and in orthopedics.  As a point of reference, patient assessment and education is approached at stages of evaluation and planning, pre-operative instruction, intraoperative and post-operative care and discharge planning for procedures that are frequently performed or are particularly problematic within their area of specialty.  Issues related to pain, its management and patient education are discussed and reviewed in the laboratory including gross dissection and classroom with attending faculty with expertise in the basic science of anatomy, pharmacology and physiology and in the clinical sciences with specialty training in pain medicine, anesthesiology, physiatry, psychiatry and the appropriate surgical specialty.  Basic knowledge is assessed before and after each training session and will similarly be evaluated throughout residency training.  It is hoped that the participants in the program will gain a better understanding of how to better evaluate pain, how and why certain management tools are selected, when they should be applied and how to help their patients understand and participate in their own care. 

The cohort of trainees was selected because residents in training are at the steepest part of their educational growth curve where information provided and reinforcement of the basics is likely to have the greatest effect.  It is also appreciated that residents play a major role in mentoring and laying down the foundations of practice for medical students at the earliest stage in medical training and a level where the emphasis on training compared to the prevalence and influence on pain healthcare is very low. In this teaching role, the residents are likely to have challenges to newly learned principles and be able to reinforce what they have learned. Finally, residents are in a position to challenge and inform attending physicians of recent advances in arts complimentary to their specialty.  I am encouraged, thus far, with the progress that this program has made and look forward to the possibility that it may impact some of the negative perceptions that we inherit when embarking on a career in pain medicine.

President’s Message: When Was That Taught?

Harry J. Gould, III MD, PhD

It has been more years than I care to admit since I graduated from medical school. As most of us have realized, with time, advances are made, with experience, skills are refined and as practitioners, we adapt to change and challenge and improve in our ability to care for patients. An unfortunate corollary to the essential fine-tuning of the evolving practitioner, especially in specialty and sub-specialty practices, is that many components of our general training are infrequently called to bear in daily practice, are less well remembered, and suffer from lack of reinforcement. I have recently been more aware of this disappointing realization both in my own practice when confronted with patients suffering with problems involving infectious disease, endocrinology, hematology, pulmonology, cardiology, and gynecology and from a different perspective, in observing the practices of colleagues who consult me for recommendations to help care for their patients in pain.  Some problems require complex solutions, but surprisingly, most can be addressed simply by returning to the basic principles learned in those early courses when we received so much “irrelevant material”.

My reason for addressing this topic is that I have noticed, more recently, probably over the last 2-3 years, that well over half of the consults directed to our in-patient consultation service for pain management have inquired as to what else can we recommend to control pain and/or whether an additional opioid medication should be added to the analgesic regimen to improve pain control for a patient. Virtually all of the presenting analgesic regimens in these cases, regardless the type of pain or pain history, include gabapentin < 300 mg daily, a muscle relaxant, and not atypically, orders for multiple formulations of mu-opioid analgesics, e.g., hydrocodone PO as needed for pain between 3-6/10 in intensity, oxycodone PO as needed for pain > 7/10 and hydromorphone IV scheduled every 3-4 hours.  The total daily morphine milligram equivalents (MME) ordered is, not infrequently, less than that in the patient’s routine outpatient regimen for chronic pain. It is possible that the initial ineffective treatment regimens have been designed in an attempt to comply with published guidelines designed to minimize opioid use, but it seems more likely that the failed attempts reflect a prevailing assumption that complex problems require complex solutions.  Obvious to a specialist, but not so to the physician with medical school a distant image in the rearview mirror of life, is that simple solutions within recommended guidelines are more often likely to produce favorable outcomes because they are less likely to introduce complications that lead to confounding results.

More efficient use of the dynamic interaction between referring physician and consultant may be the best way improve patient care because the best learning opportunities seem to occur when therapeutic approaches are introduced or reviewed in the context of administering in real-time to an interesting patient or a problem situation (“When I was a resident, I had a patient that…”) and take less time out of a busy practitioner’s day than a formal course for review.  A referral for consultation provides a platform for the specialist to offer a focused review of basics from their specialty that reinforce optimum therapeutic approaches for managing a given problem and a platform for the referring team to provide feedback to the specialist as to the rationale for either accepting or declining to implement a given recommendation.

In the offered example, a good place to start might be to determine and establish an analgesic treatment base before embarking on diagnostic tests or therapeutic treatments that are likely to produce additional pain. The process of determination would be comprised of an assessment of the type of pain that is being experienced, a determination of co-morbid problems and whether the patient has had or is currently receiving medications, especially opioids, for a previous acute or a chronic problem, for which medications had been used and if current, what dose is being taken. It also would seem reasonable to take advantage of prior history and to start with a medication that has been shown to be effective for the particular patient and to anticipate that any new pain may require MME dosing equal or greater than the premorbid regimen to achieve adequate pain control and to prevent the onset of withdrawal symptoms. The pharmacologic principles that simple, monotherapy regimens are easier to administer, have higher rates of compliance and are more effective are generally good principles to follow when designing a treatment regimen.  Mu-opioid agonists due to chemical configuration and available routes of administration have different benefit potential and different side effect profiles that provide the basis of therapeutic selection.  Unfortunately, analgesic benefits of mu-agonists are achieved through a single mechanism of action, regardless the formulation precluding a hoped for reduction of daily MME by providing treatment with multiple mu-opioid agonist at low doses. Furthermore, the simultaneous initiation of treatment with multiple formulations complicates the recognition of which agent(s) might be responsible for any benefits or adverse effects observed.  Because of incomplete cross-tolerance between mu-opioid agonists, the concurrent use of multiple formulations, also effectively eliminates or greatly reduces any possibility for drug rotation, if needed. Thus, selecting a single mu-agonist formulation, determining the route of administration and the proper dosing allows for early identification of tolerance and dosing efficacy. Finally, the use and selection of potentially beneficial adjuvant agents based on pain type and benefits that may be realized from their otherwise adverse, side effect profile, e.g., drowsiness in patients with difficulties sleeping, are important components of the analgesic regimen that are likely to produce benefit without undesired adverse effects if they are prescribed in adequate doses. 

In the midst of the exponential growth in technology and continued advances in the era of information explosion that often lead to overwhelming increases in system complexity, it may be comforting to remember that the old, simple, basic principles that we learned as fledgling healthcare providers are still useful and may be our best means for caring for our modern day patients in a rapidly expanding and changing world of pain medicine.

Treatment of Refractory Chronic Migraine With Worm Eggs: A Therapy Rooted in Evolution

Lawrence Robbins, MD and Hanah Alley, MD

(originally published in Medicine Connections, 2021 vol.1, issue 2: a journal of the World Headache Society)

Abstract

Introduction: This was a small open label study designed to determine efficacy of helminth egg therapy in refractory chronic migraine (RCM) patients. It is probable that the immune system is involved in migraine.1 Helminth worms have populated the GI tract of primates for millions of years. They downregulate the immune response. When the helminths (and other parasites) are removed, the result may be an increase in autoimmune illness. The immune system and inflammation are involved in migraine pathophysiology.

Study design:  Eleven RCM patients were enrolled. After the run-in period, patients ingested the helminth eggs every 2 weeks for 5 months.  These eggs were from the pig whipworm, T. suris. The primary endpoint involved the number of moderate or severe headache days per month. The first (run-in) month was compared to the last 2 months of active therapy. Secondary endpoints included disability, depression, anxiety, and quality of life.

Results:  5 of 11 patients met the primary endpoint (a reduction in moderate or severe headache days by at least 3 per month). The number of moderate or severe headache days decreased by 14, 10, 8, 7, and 3 in these patients.

The patients who met the primary endpoint all began with essentially no clinical depression at baseline.  Disability declined in all 5 patients, as did anxiety. Quality of life (number of unhealthy days per month) improved in 2 of the 5 patients who met the primary endpoint.

4 of 11 patients who completed the study did not meet the primary endpoint. 1 other patient did not supply data, and another discontinued treatment due to diarrhea. Analysis of their secondary endpoints did not result in any definitive conclusions as to why they did not improve.

Conclusion:  This study indicates that there may possibly be a role for helminth therapy in treating refractory chronic migraineurs. 5 of 11 patients did well. This treatment is rooted in evolution. The presence of helminths results in a downregulation of certain aspects of our immune system. By re-introducing helminths into the GI system, we may dampen our immune response. This may possibly help in the treatment of conditions that involve the immune system, such as migraine.

Keywords:  Migraine, Refractory Migraine, Headache, Helminth,  Evolution, Chronic Migraine, long haul Covid worm eggs,

Introduction

The concept of migraine as an autoimmune entity has been discussed for many years.1 Migraine is a common disabling neurological disorder. Despite available therapies, a subset of patients remains unresponsive to preventive treatment. Individuals with Refractory Chronic Migraine (RCM) have failed a number of the available preventatives, and suffer from frequent moderate or severe headaches2,5. Individuals with Chronic Migraine (CM) are those with a headache occurring on 15 or more days/month for more than 3 months.  For at least 8 days/month their headaches are migrainous.4,6  The pathophysiology of migraine is interwoven with the immune system, which is the reason for the current study7,8.

Helminth worms have co-existed in primates for millions of years. Helminths, along with other parasites, downregulate the human immune response. In many human populations, the helminths have largely been eradicated. This resulted in an increase in autoimmune illness. 9,10,11,12,16,17,18.

There is a robust literature, dating back more than 20 years, introducing helminth eggs into the GI tract of those with various autoimmune illnesses. 

Helminth therapy has been extensively evaluated for its safety and efficacy in the context of autoimmune diseases9,10,11,15. These include Inflammatory Bowel Disease (IBD)9,10,12, Type 1 Diabetes Mellitus (T1DM) 16,17 and Systemic Lupus Erythematosus (SLE)12,13,18. Helminths elicit an immune response by promoting production of anti-inflammatory mediators14,15,19,.  The result is to downregulate the host immune response to various antigens9 .

Helminths have lived in the GI tract of primates for millions of years.  Over time, a homeostasis was achieved between the parasites and the host immune system.  The host primate’s immune system has been downregulated in response to the helminths. It is easy and relatively safe to reintroduce helminth eggs into the GI tract.  This study was undertaken in order to assess the effect of introducing helminth eggs into the GI system of patients with refractory chronic migraine.

Materials/Methods:   

Study patients:  Eleven patients (10 women, 1 man) with the diagnosis of refractory chronic migraine were enrolled in the study. Refractory chronic migraine was defined according to the European federation consensus.2 They were patients well known to the treating physician.  Ages ranged from 25 to 67. Patients’ names and information were de-identified.

Study Design: This was an open label study designed to determine efficacy of helminth egg therapy in refractory chronic migraine patients. The study included a one-month run-in prior to the actual treatment phase.  Patients then were to receive the helminth eggs every 2 weeks for 5 months.  There were 11 total doses of the eggs.  Patients kept daily track of the headache severity. They used a simple paper calendar.  A visual analog scale, 1 to 10, was utilized. A headache day was considered moderate to severe if the severity was rated 5 or greater. Mild days were listed but did not count for the purpose of this study. IRB approval was obtained. The IRB was through Advarra: PRO ID# 00051859, CR 00316902.  Possible risks were explained, and written consent was obtained.

The patients were allowed to remain on stable preventive medication/approaches. They were asked not to add new preventive medication or approaches. To our knowledge, none of the patient received new preventive medication during the study.

Safety of the Eggs: The eggs are from the whipworm, Trichuris suis. Safety of these eggs has been evaluated for 20+ years. There have been various studies, primarily regarding autoimmune illnesses.  Patients have also been able to order the eggs from the Tanawisa Company. Over 36,000 patients have ingested the eggs. There is a helminth therapy Facebook group.  The eggs have not produced adverse effects, except for occasional mild diarrhea14. There was one instance of eggs maturing into actual worms (which are benign). The company stated that it was unclear whether the eggs actually contributed to that one case.  We had multiple conversations with the Tanawisa Company regarding safety. The eggs are contained in a solution with 98% viable eggs. These attach to the mucosa surrounding the caecum. The eggs release molecules that induce regulatory T-cells by the human host. In theory, with a severely compromised GI mucosa, the eggs could attach and hatch, although this has not happened in the studies involving GI illness. We did not allow patients with GI mucosal illnesses to participate. The eggs “modulate” the immune system, but have not resulted in infections or immune deficiency issues. The eggs were donated by Tanawisa, the company that produces them. The company has extensive safety and efficacy information on Tanawisa.com.  The results of the studies, and extensive information on safety and risks, were given to all patients as part of the informed consent.  A number of these studies are listed in the reference section below. There has been no evidence that the egg exposure actually compromises the immune system, or leads to infection or immune based problems.

Patient visits and lab tests:  Patients were seen in person prior to the run-in month, after 1 month, after the 3rd month, and after the 6th month. Patients were given the egg solutions to ingest every 2 weeks, and the solutions were stored in their refrigerators. In addition, phone visits were done after the 2nd, 4th, and 5th months. A physical exam was performed on the first visit, at the 3rd visit, and after the final visit. An ECG was performed prior to the study. Blood tests (cbc, cmp, TSH, T4, sedimentation rate, ANA, and Hemoglobin A1c) were drawn 2 times: prior to month 1, and after month 3. All visits and blood tests were at no cost to the patient.  

Screening tests: These were done prior to the study, and after the last visit. The screens included the Beck Depression Inventory, the Beck Anxiety Inventory, Migraine Disability Assessment Test (MIDAS), and the Health Related Quality of Life Measure (number of unhealthy days per month).

Beck Depression Inventory:  1 to 10=none, 11 to 16=mild mood disturbance, 17 to 20= borderline clinical depression, 21-30=moderate depression, 31 to 40= severe depression, 40 or more=extreme depression.

Beck Anxiety Inventory:  0 to 7=none or minimal, 8 to 15=mild, 16 to 25= moderate, 26 to 63=severe.

MIDAS:  0 to 5=little or no disability, 6 to 10= mild, 11 to 20=moderate, 21 or more=severe.

HRQOL:  # of unhealthy days per month: maximum number= 30 days per month

Refractory Chronic Migraine Severity Scale: This scale was developed by Lawrence Robbins, and separates patients into mild, moderate, and refractory chronic migraine. Ten criteria are used in the scale. (5)

Inclusion Criteria: Patients known to the Robbins Headache Clinic, 18 to 70 years old.  Each patient had a well-established diagnosis of chronic migraine, according to ICHD-3 criteria (4). Every patient had the diagnosis of refractory chronic migraine (RCM)(2). The patients were graded as to the severity of the RCM (5).

Exclusion Criteria:  1. Patients with IBS-D or other gastrointestinal conditions that would result in diarrhea. Patients with a compromised GI mucosa due to a GI illness were excluded, 2. Severe psychiatric or medical illness which, in the judgment of the PI, might endanger the patient, 3. Use of probiotics during the course of the trial, 4. Inability to adequately track the headaches and side effects, Any other condition that would interfere with the ability of the patient to successfully complete the study, and 6. Pregnancy: See pregnancy section below.

Medication Use: Patients were allowed to continue on their usual medications. If possible, patients were encouraged not to change the dosage of their preventive medications. They were also asked not to start new preventive medications. If necessary, medications changes were allowed. If patients needed to take an antibiotic that opposed the action of the egg solution, they would be discontinued from the study.

No patients changed preventives during the trial. The doses of their pre-existing preventives were kept steady throughout the trial.

Pregnancy:  There is not enough evidence to state that the eggs are safe for use during pregnancy. If pregnancy was being considered, the patient was excluded from entering the study. For those women where pregnancy was not being considered, but was possible, adequate birth control methods were to be employed. To our knowledge no patient became pregnant during the trial.

Safety Monitoring and Adverse Events/Adverse Effects:  Dr. Robbins or the study coordinator conducted monthly discussions with each patient about adverse events and adverse effects.  Patients were encouraged to report any new effects, particularly GI adverse effects.

Primary endpoint: The number of moderate or severe headache days during months 5 and 6 (average of the 2 months), as compared to the number of moderate or severe headache days during the run-in period (first 30days).   Success is a decrease in monthly moderate or severe headache days by 3 or more days per month. Moderate or severe was a 5 or greater on the 1 to 10 severity scale.   

Secondary endpoints: 1. Disability assessment before and after the study (MIDAS), 2. Evaluation of depression before and after the study (Beck Depression Inventory),  3. Comparison of anxiety after the study versus during the run-in phase (Beck Anxiety Inventory) and 4. Evaluation of a quality of life assessment before and after the study (Health-Related Quality of Life Scale, as measured by the number of unhealthy days per month).

Results

Patient #1: 42 y.o. F with moderate refractory chronic migraine (RCM).

Pre-study month (run-in) # of moderate or severe headache days: 30

Month #1 (active study): 30 moderate to severe days

Month #2: 24 days

Month #3: 24 days

Month #4: 22 days

Month #5: 22 days

Midas (disability): pre-study=51, post-study=30

Beck Depression: pre-study=0, post-study=1

Beck Anxiety: pre-study=6, post-study=3

QOL: pre-study # of unhealthy days per month=30, post-study (the last month)=26

Summary: The # of moderate or severe headache days did decrease from 30 to 22 (average of the last 2 months). Disability remained high but improved. Depression was low (pre and post) and anxiety, which was mild pre-study, did lessen.

Patient #2: 39 y.o. F with mild RCM.

Pre-study month (run-in): 20 moderate or severe headache days(and 6 mild days)

1st  (active) month: moderate to severe days: 13

2nd month: 15

3rd month: 12

4th month: 8

5th month: 6

Midas: pre-study= 18, post-study=9

Beck Depression: pre-study=0, post-study=0

Beck Anxiety: pre-study=5, post-study=3

QOL: pre-study= 0, unhealthy days, post-study= 0

Summary: The # of moderate or severe headache days decreased from 20 pre-study to 7 (average of the last 2 months). Midas disability improved. Depression was low and anxiety, which was low, did improve.

Patient #3  36 y.o. F with moderate RCM.

Pre-study month (run-in): 9 moderate to severe headache days(and 11 mild days)

1st month (active): 7 moderate to severe days

2nd month: 3

3rd month: 2

4th month: 2

5th month: 2

Midas: pre-study=15, post-study=8

Beck Depression: pre-study=0, post-study=0

Beck Anxiety: pre-study=3, post-study=0

QOL: pre-study=7 unhealthy days, post-study= 0

Summary: The # of moderate to severe headache days decreased from 9 pre-study to 2 (average of the last 2 months).  Midas disability improved. There was no depression, and anxiety, which was low, did improve. The # of unhealthy days dropped significantly.

Patient #4   68 y.o. F with moderate RCM.

Pre-study month (run-in): 15 moderate to severe headache days(and 7 mild days)

1st month (active): 11 moderate to severe days

2nd month: 5

3rd month: 5

4th month: 5

5th month: 2

Midas: pre-study=42, post-study=30

Beck depression: pre-study=7, post-study=8

Beck anxiety: pre-study=12, post-study=8

QOL: pre-study=4 unhealthy days, post-study=4

Summary: The # of moderate to severe headache days decreased from 15 pre-study to 3.5 (average of the last 2 months).  Midas disability improved. Depression did not change, and anxiety improved.  The # of unhealthy days remained the same.

Patient #5 65 y.o F with severe RCM.

Pre-study (run-in): 8 moderate to severe headache days(and 12 mild days)

1st month (active): 9 moderate to severe days

2nd month: 4

3rd month: 5

4th month: 5

5th month: not recorded

Midas: pre-study= 131, post=100

Beck depression: pre-study=4, post=6

Beck anxiety: pre-study=23, post=5

QOL: pre-study=30 unhealthy days, post=30

Summary: The # of moderate to severe headache days decreased from 8 pre-study to 5 (4th month). Midas disability improved. Depression was slightly worse from pre-study to month 4. Anxiety improved significantly. The # of unhealthy days remained the same.

Patient #6  55 y.o. with moderate RCM.

Pre-study (run-in): 30 moderate to severe headache days

1st month (active): 28 moderate to severe days

2nd month: 30

3rd month: 30

4th month: 26

5th month: 29

Midas: pre-study=25, post=12

Beck depression: pre-study=3, post=3

Beck anxiety: pre-study=10, post=10

QOL: pre-study=10 unhealthy days, post=6

Summary: the # of moderate to severe headache days decreased from 30 pre-study to 27.5 (average of 4th and 5th month). Midas disability improved.  Depression was low, and did not change. Anxiety remained unchanged. The # of unhealthy days improved.

Patient #7  24 y.o. M with severe RCM

Pre-study (run-in): 30 moderate to severe days

1st month (active) and months 2 thru 5: 30 moderate to severe days each month

Midas: pre-study=210  (post-study not done)

Beck depression: pre-study= 27  (post-study not done)

Beck anxiety pre-study= 22   (post-study not done)

QOL: pre-study=27 unhealthy days  (post-study not done)

Summary: the # of moderate to severe headache days did not change (30 days per month). This patient did not complete post-study surveys. Pre-study his Midas revealed high disability. Depression and anxiety were significant.

Patient #8: 64 y.o. F with severe RCM.

Pre-study (run-in): 19 moderate to severe headache days(and 6 mild days)

1st month (active study): 22 moderate to severe days

2nd month: 20 moderate to severe days

3rd month: 17

4th month: 22

5th month: 20

Midas disability: pre-study=23, post=26  (post-study not done)

Beck depression: pre-study=26  (post not done)

Beck anxiety: pre-study=21  (post not done)

QO: pre-study=30 unhealthy days  (post not done)

Summary: The # of moderate to severe headache days increased slightly by the 5th month. Disability, depression, and anxiety levels were high (post-study surveys were not done). Pre-study every day of the month was an unhealthy day.

Patient #9:  34 y.o. F with severe RCM

Pre-study (run-in): 21 moderate to severe headache days(and 9 mild days)

1st month (active study): 21 moderate to severe days

2nd month: 19

3rd month: 22

4th month: 23

5th month: 23

Midas disability: pre-study=42, post-study=30

Beck depression: pre-study= 0, post=0

Beck anxiety: pre-study=3, post=2

QOL: pre-study=24 unhealthy days, post=23

Summary: the # of moderate to severe headache days were slightly increased by the 5th month. Disability improved somewhat. There was no depression, and mild anxiety was unchanged.  The # of unhealthy days was essentially unchanged.

Patient #10:  62 y.o F  Severe RCM.

Pre-study:  moderate or severe headache days: 30

This patient did ingest the eggs but no headache data was captured.

Patient #11: 39 y.o. F  Moderate RCM.

Pre-study: moderate to severe headache days: 30. This patient ingested only one dose of the eggs. She subsequently had GI upset and mild diarrhea. She discontinued the therapy. Over the ensuing 4 months, the GI upset and diarrhea improved but did not resolve. GI work-up was pending. The headaches remained unchanged.

Lab tests/ECG:  blood tests were drawn prior to the study, and after the 3rd month. There were no abnormal tests that resulted from the treatment. ECGs did not reveal significant abnormalities.

Summary of Results

5 of 11 patients met the primary endpoint (a reduction in moderate or severe headache days by at least 3 per month). The number of moderate or severe headache days decreased by 14, 10, 8, 7, and 3 in these patients.

The patients who met the primary endpoint all began with essentially no clinical depression at baseline.  Disability declined in all 5 patients, as did anxiety. Quality of life (number of unhealthy days per month) improved in 2 patients and remained the same in 3 patients.

4 of 11 patients did not meet the primary endpoint. 1 patient did not supply data, and another discontinued due to diarrhea. Analysis of their secondary endpoints did not result in any definitive conclusions as to why they did not have a successful trial.

Discussion

Eleven patients with refractory chronic migraine were enrolled. Five patients met the primary endpoint.  The 5 patients experienced a decrease in moderate to severe headache days per month of 14 days, 10 days, 8 days, 7 days, and 3 days. Four of the remaining patients finished the study but did not incur any benefit.  One patient did not provide data, and another discontinued the eggs due to diarrhea.  That was the only adverse effect observed in the trial.

The 5 patients who experienced a decrease in the number of moderate to severe headaches also observed a significant lessening of disability. All of these 5 patients had low baseline depression scores.

This was a small open label study that included patients with refractory chronic migraine. They ingested helminth eggs for 5 months. The purpose of the eggs was to downregulate the immune response. Helminths may modulate the immune system via release of excretory/secretory proteins. The cell mediated inflammation may be modulated by the helminth eggs. While the helminth eggs modulate immune activity, there has been no evidence for harm. Tdhe concept of migraine as an autoimmune illness, or at least involving the immune system, has been debated and discussed for decades.1 This study is rooted in evolution. For millions of years the GI tract of primates (and other animals) has been colonized by various worms or other parasites.  It has only been recently, in the past hundred years, that helminths and other parasites have been eradicated from human GI tracts.  This has been accomplished through improved sanitation as well as the introduction of clean water and food.

The role of helminth therapy has been discussed in the introduction section (above).  The studies have involved introducing helminth eggs into patients suffering from various autoimmune illnesses.  

There have been 12 helminth therapy studies conducted for various autoimmune diseases9,10,11,15.  The use of helminthes for various autoimmune disorders has met with reasonable success, with minimal adverse effects. The study on Inflammatory Bowel Disease (IBD)9,10,12 revealed that this may be a viable therapy, and that the eggs appear to be safe.  A study on Type 1 Diabetes Mellitus (T1DM) 16,17 also indicated that the eggs are safe for human consumption. This was also confirmed in a study involving the eggs and Systemic Lupus Erythematosus (SLE)12,13,18.  

Conclusion: This small study indicates that there may be a role for helminth therapy in the treatment of refractory chronic migraineurs. This approach is rooted in evolution. We ignore evolution at our peril. For millions of years helminths and other parasites have populated the GI tract of animals. The presence of helminths results in a downregulation of certain aspects of our immune system. By re-introducing helminths into the GI system, we may dampen our immune response. This may aid in the treatment of migraine headache.  A randomized, placebo-controlled trial would be welcome.

Acknowledgments

Diana Delatre was the study coordinator. The Tanawisa Company donated the eggs for the study. Other than donating the eggs, the company did not play a role in the study.  

Conflicts of interest: none

NOTE: This therapy could be helpful for long haul Covid symptoms, if studies revealed sufficient efficacy…

References

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  2. Sacco S, Braschinsky M, Ducros A, et al. European headache federation consensus on the definition of resistant and refractory migraine: Developed with the endorsement of the European Migraine & Headache Alliance (EMHA). J Headache Pain. 2020;21(1):76. Published 2020 Jun 16. doi:10.1186/s10194-020-01130-5
  3. Schulman EA, Lake AE 3rd, Goadsby PJ, Peterlin BL, Siegel SE, Markley HG, Lipton RB. Defining refractory migraine and refractory chronic migraine: proposed criteria from the Refractory Headache Special Interest Section of the American Headache Society. Headache. 2008 Jun;48(6):778-82. doi: 10.1111/j.1526-4610.2008.01132.x. Epub 2008 May 14. PMID: 18484982.
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  7. Malhotra R. Understanding migraine: Potential role of neurogenic inflammation. Ann Indian Acad Neurol. 2016;19(2):175-182. doi:10.4103/0972-2327.182302
  8. Koyuncu Irmak D, Kilinc E, Tore F. Shared fate of meningeal mast cells and sensory neurons in migraine. Front Cell Neurosci. 2019;13:136. Published 2019 Apr 5. doi:10.3389/fncel.2019.00136
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  13. Aprahamian TR, Zhong X, Amir S, et al. The immunomodulatory parasitic worm product ES-62 reduces lupus-associated accelerated atherosclerosis in a mouse model. Int J Parasitol. 2015;45(4):203-207. doi:10.1016/j.ijpara.2014.12.006
  14. Huang X, Zeng LR, Chen FS, Zhu JP, Zhu MH. Trichuris suis ova therapy in inflammatory bowel disease: A meta-analysis. Medicine (Baltimore). 2018;97(34):e12087. doi:10.1097/MD.0000000000012087
  15. Leroux LP, Nasr M, Valanparambil R, et al. Analysis of the Trichuris suis excretory/secretory proteins as a function of life cycle stage and their immunomodulatory properties. Sci Rep. 2018;8(1):15921. Published 2018 Oct 29. doi:10.1038/s41598-018-34174-4
  16. Zaccone P, Hall SW. Helminth infection and type 1 diabetes. Rev Diabet Stud. 2012;9(4):272-286. doi:10.1900/RDS.2012.9.272
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  18. Rodgers DT, Pineda MA, Suckling CJ, Harnett W, Harnett MM. Drug-like analogues of the parasitic worm-derived immunomodulator ES-62 are therapeutic in the MRL/Lpr model of systemic lupus erythematosus. Lupus. 2015;24(13):1437-1442. doi:10.1177/0961203315591031
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The Bipolar Spectrum In Pain Patients: Recognition and Management

Olivia Lee and Lawrence Robbins, MD

Introduction to Bipolar Disorder

The broadening concept of the bipolar spectrum has evolved over the years. We no longer view bipolar primarily as characterized by mania. Bipolar disorder is a chronic psychiatric illness that is broadly categorized in the DSM-V into several subtypes – bipolar I and bipolar II – depending on the presence of depressive, manic, or hypomanic features. It may occur in at least 4.4% of the population, but this number is likely to underestimate the true prevalence.1 There are major issues in identifying the milder bipolar presentations.2 Bipolar disorder often co-occurs with other psychiatric illnesses, creating innumerable patient presentations that may not fit neatly into the boxes of the two subtypes. The word “bipolar” is misleading and creates a stigma of severe mental illness.  There certainly is underdiagnosis for the milder forms. Most patients do not suffer from classic manic symptoms. The milder “hypomanias” are subtle and mild in comparison to true mania. For most patients there is a significant lag time from the onset of milder bipolar symptoms and diagnosis.

The classic mania that defines bipolar I is easily recognized.  Symptoms of mania include euphoric mood, grandiosity, distractibility, flight of ideas, thoughtlessness or risk-taking, and excessive involvement in pleasurable activities (i.e., sex, gambling, spending). Patients in the midst of a manic episode may also take on an excessive number of activities and exhibit pressured speech, excessive speech, irritability, and insomnia.3 These behaviors cause serious impairment to daily functioning and often last for several days or longer. Acutely manic patients are also high risk for harm to themselves or others.4

Milder hypomania is less likely to impair everyday functioning. However, it is also hypomania that is more commonly missed for a variety of reasons.4 Hypomania and the milder end of the bipolar spectrum have various presentations, complicating the diagnosis. These patients may have persistently agitated personalities, with frequent depression or excessive energy but not meeting the classic diagnostic criteria for bipolar I or bipolar II. Brooding, irritable pessimism may be a manifestation of the milder end. They often have a family history of bipolar disorder or depression. Many do not identify or remember a clear hypomanic episode. Diagnosing and treating these patients greatly improves  quality of life and reduces mortality risk from suicide. The clinical stakes for missing bipolarity are enormous.

Speaking with a “significant other” is vital for teasing out mild hypomanic symptoms.4 Most patient simply complain of depression. Signs of mild bipolar disorder may include a history of early onset depression(prior to age 18), severe bouts of depression, rapid onset depression for no apparent reason, poor response to trials of antidepressants (including complaints of being up all night, mind racing, etc.), agitation, anger, high anxiety, hypersomnia or (less likely) insomnia, and irritability. Family history of severe depression, hospitalization, and other bipolar traits is helpful. The “bipolar reaction” to antidepressants may give insight into underlying bipolar disorder.4 Family history of a bipolar reaction to antidepressants may also be a clue. An opposite reaction to other drugs may be present, such as being anxious or wired from benzodiazepines or sleeping pills. Depression is often the primary problem in bipolar II disorder; it is much more pervasive than are the highs of hypomania. Comorbid moderate or severe anxiety may further compound impairment seen in bipolar depression and increase suicidal tendencies by up to 35%.5 Suicide and substance abuse are commonly found among those with untreated bipolar.

Comorbidity of Chronic Pain and Bipolar Disorder

Bipolar disorder patients who also suffer from chronic pain are challenging. Almost 24% of bipolar patients may present with chronic pain.6 The comorbid pain decreases quality of life. Patients with bipolar disorder and chronic pain often respond poorly to treatment and have an increased risk of suicide.6 One study that assessed the relationship between pain and bipolar disorder recommended a pain assessment as part of the routine care for patients suffering from bipolar.6  It requires a multidisciplinary approach to adequately treat these patients. Other than the pain physician/provider, psychotherapists constitute a vital part of the team.

Comorbidity of Migraines and Bipolar Disorder

The comorbidity of migraine with mood disorders has been well documented.  There have been a number of clinic based studies as well as epidemiologic samples from community populations.7 Migraine and depression share some of the same pathophysiology.  Antidepressants or mood stabilizers may alleviate both conditions. In the majority of migraine patients who suffer from depression, anxiety is a complicating factor. The anxiety disorder often precedes the age of onset of migraine, with depression following afterward. Migraine or other pain may exacerbate depression, and depression fuels migraine and pain.  This is in addition to the shared environmental and genetic factors linking migraine and depression.

Emerging data is identifying the relationship between bipolar disorder and migraine. From 25 to 35% of bipolar patients suffer from migraine as well.6  This association may be due to shared pathophysiologic mechanisms.

Treatment Approaches for Bipolar Disorder

It may take some time to find the effective medication, or medications, for a given patient. Mood stabilizers often are the mainstay of treatment, and sometimes help the  headaches. The anticonvulsants, lithium, and the atypicals constitute the 3 classes of mood stabilizers. Lamotrigine is the most commonly used antiepileptic for bipolar, but does not help headaches. Lamotrigine may be beneficial for some with neuropathic pain. Divalproex sodium is effective for mania, hypomania, depression associated with bipolar disorder, and for migraine prevention. Divalproex has been well studied for these conditions and is one of the most commonly used migraine preventives. Carbamazepine and oxcarbazepine are antiepileptics that have utility as mood stabilizers, but not for migraine prophylaxis. They may alleviate neuropathic pain. Oxcarbazepine is somewhat safer than the original carbamazepine. Gabapentin has been effective in high doses for some patients with milder bipolar symptoms. Gabapentin is effective for certain pain syndromes, but not for migraine.

Lithium carbonate is an underutilized mood stabilizer. Low doses of lithium do not usually cause hypothyroidism or irritate the kidneys. With appropriate monitoring these risks can usually be avoided.  Lithium sometimes alleviates cluster headaches.  Lithium has also been evaluated for conditions such as multiple sclerosis and Alzheimer’s.8

Divalproex sodium, carbamazepine, and oxcarbazepine may produce teratogenic effects. Divalproex is more likely than the others to result in birth defects, particularly at doses above 500mg daily. Lamotrigine may be the best choice of an antiepileptic during pregnancy.  Lithium taken during pregnancy is fetal cardiac anomalies, but this is rare.  Lithium may be indicated for bipolar during pregnancy disorder under appropriate circumstances.8–10 For women who were stable on lithium prior to pregnancy, discontinuation during pregnancy may lead to relapse.10

Atypical antipsychotics are also a mainstay for bipolar symptoms.11 These agents include the general categories of “pines”, “dones”, “pips” and “rips”. These include clozapine(the first atypical), olanzapine, quetiapine, risperdone, lurasidone,  brexpiprazole, aripiprazole, and cariprazine.These are efficacious in treating mania and are prescribed as monotherapy or in combination with another mood stabilizer.12 The atypical side effects are many and varied. These include metabolic syndrome (insulin resistance, dyslipidemia, hypertension), weight gain, fatigue, “brain fog”, and extrapyramidal symptoms (akathisia, acute dystonia, dyskinesia/parkinsonism, and tardive dyskinesia).13 Patients on atypical antipsychotics  should receive routine bloodwork.  Signs of EPS may go unnoticed by some patients, rendering it important to ask specific questions. There certainly are concerns about the atypical antipsychotics during pregnancy, but in low doses these have resulted in minimal problems in the newborns.

As previously mentioned, lamotrigine is a very commonly prescribed mood stabilizer for bipolar disorder. It is one of the only effective medications for bipolar depression.14 Initiating a patient on lamotrigine requires a slow titration due to the rare (1:3,000: according to the German rash registry) but lethal side effects of Stevens Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN).15 SJS/TEN are variants of the same hypersensitivity reaction, differentiated by the percent of skin surface area that is affected (<10% in SJS, >30% in TEN). This rare rash is characterized by painful blisters, peeling skin, and tissue necrosis. The SJS rash often occurs in unusual areas, such as the palms of the hands, soles of the feet, or mucous membranes. A “regular” drug rash may occur in up to 10% of patients. Signs of SJS/TEN typically occur within 8 weeks of initiation and warrant immediate discontinuation of lamotrigine.15 Many of the anticonvulsants carry the risk of SJS/TEN, such as divalproex, carbamazepine, and oxcarbazepine.

 

Patients with bipolar spend the vast majority of their time in depression rather than in mania. Many of these patients require combination therapy to target depressive symptoms. Lamotrigine and quetiapine are two of the atypicals that may be effective in managing depressive episodes.16 While lithium is a first line therapy for mania, it has also shown efficacy in preventing relapse of depressive episodes and decreasing suicidality.16 Combination therapy of olanzapine and fluoxetine has been approved by the FDA for treating depression associated with bipolar I disorder.16 Lurasidone is an atypical that has shown promise for the depression.4,17 Antidepressants usually result in either no effect, or the typical “bipolar” response (up all night, wired, mind racing). Occasionally they are helpful. Emerging therapies include, among others, ketamine, TMS, and microdosing (primarily psilocybin).16

Conclusion

It is crucial to recognize psychiatric disorders in our pain patients. Patients with unrecognized personality disorders or bipolar disorder often suffer from poor outcomes. Patients with the milder end of the bipolar spectrum frequently are diagnosed and treated as if they suffer from “regular” depression. They generally do not do well on antidepressants.  Patients with psychiatric comorbidities, such as bipolar, require a multidisciplinary approach. The medications that treat psychiatric conditions may also be helpful for the pain conditions as well.

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 associate 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 lrobb98@icloud.com.

Sources

  1. Harvard Medical School. National Comorbidity Survey (NSC).; 2007.
  2. Kessler RC, Wai TC, Demler O, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):617-627.
  3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington D.C: American Psychiatric Press; 2013.
  4. Culpepper L. The diagnosis and treatment of bipolar disorder: Decision-making in primary care. Prim Care Companion J Clin Psychiatry. 2014;16(3). doi:10.4088/PCC.13r01609
  5. Amuk OC, Patel RS. Comorbid Anxiety Increases Suicidal Risk in Bipolar Depression: Analysis of 9720 Adolescent Inpatients. Behav Sci (Basel). 2020;10(7). doi:10.3390/BS10070108
  6. Stubbs B, Eggermont L, Mitchell AJ, et al. The prevalence of pain in bipolar disorder: A systematic review and large-scale meta-analysis. Acta Psychiatr Scand. 2015;131(2):75-88. doi:10.1111/acps.12325
  7. KR M, DE S. Comorbidity of migraine and psychiatric disorders. Neurol Clin. 1997;15(1):115-123. doi:10.1016/S0733-8619(05)70298-X
  8. L L, B C, A N, et al. Lithium Use During Pregnancy in a Patient With Bipolar Disorder and Multiple Sclerosis. Clin Neuropharmacol. 2020;43(5):158-161. doi:10.1097/WNF.0000000000000407
  9. Jones SC, Jones I. Pharmacological Management of Bipolar Disorder in Pregnancy. CNS Drugs. 2017;31(9):737-745. doi:10.1007/s40263-017-0452-x
  10. Yacobi S, Ornoy A. Is lithium a real teratogen? What can we conclude from the prospective versus retrospective studies? A review. Isr J Psychiatry Relat Sci. 2008;45(2):95-106.
  11. JR C, PE K, W M, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162(7):1351-1360. doi:10.1176/APPI.AJP.162.7.1351
  12. Canadian Agency for Drugs and Technologies in Health. Combination Atypical Antipsychotics in Adolescents or Adults with Bipolar Disorder with Psychotic Features: A Review of Clinical and Cost-Effectiveness and Guidelines.; 2016. https://pubmed.ncbi.nlm.nih.gov/27831672/. Accessed August 15, 2021.
  13. Stroup TS, Gray N. Management of Common Adverse Effects of Antipsychotic Medications. doi:10.1002/wps.20567
  14. Ng F, Hallam K, Lucas N, Berk M. The Role of Lamotrigine in the Management of Bipolar Disorder. Vol 3.; 2007.
  15. Messenheimer J, Mullens EL, Giorgi L, Young F. Safety review of adult clinical trial experience with lamotrigine. Drug Saf. 1998;18(4):281-296. doi:10.2165/00002018-199818040-00004
  16. Yalin N, Young AH. Pharmacological treatment of bipolar depression: What are the current and emerging options? Neuropsychiatr Dis Treat. 2020;16:1459-1472. doi:10.2147/NDT.S245166
  17. Ostacher M, Ng-Mak D, Patel P, Ntais D, Schlueter M, Loebel A. Lurasidone compared to other atypical antipsychotic monotherapies for bipolar depression: A systematic review and network meta-analysis. World J Biol Psychiatry. 2018;19(8):586-601. doi:10.1080/15622975.2017.1285050

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. 

Long Haul COVID-19

Olivia Lee and Lawrence Robbins, MD

Introduction

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.

Treatments

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

Conclusion

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 lrobb98@icloud.com.

Resources

  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. https://www.researchgate.net/publication/344318845_post_acute_or_prolonged_COVID-19_ivermectin_treatment_for_patients_with_persistent_symptoms_or_post_acute. 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. https://www.businesswire.com/news/home/20210216005737/en/. 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. https://web.musc.edu/about/news-center/2020/11/16/musc-study-to-address-post-covid-neurological-and-psychiatric-symptoms-using-at-home-format. Published November 16, 2020. Accessed June 27, 2021.

ANA2021 Registration Is Now Open!

ANA2021’s Virtual Annual Meeting is set for October 17-19 with an Opening Symposium on October 16 and registration is now open!

All full registrations include access to the ANA2021 Meeting Recordings package, ensuring you won’t miss out on the latest neurological research even if your schedule should change. Registration also includes complimentary access to the SIG Series featuring virtual presentations related to ANA’s Special Interest Groups. These 18 sessions will be presented on select dates throughout November and December so you can attend as many as you’d like. 

 

ANA2021 is the top meeting for academic neurologists and neuroscientists at every career stage to convene over groundbreaking research and best practices for success in the field. Click here to view the Advance Program. 

 

Don’t miss this opportunity to learn from and connect with the best and brightest in the field – register for ANA2021 today!

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.

 

References

 

  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. https://doi.org/10.1111/head.13951
  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. https://doi.org/10.1111/head13956
  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 practicalpainmanagement.com, 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.

Back to the Basics: Managing Pain Months After COVID-19

Harry Gould, MD, PhD

A year ago, the United States was in the midst of understanding and dealing with the complexities of the “Opioid Epidemic”, what until then had been considered the greatest healthcare crisis in U.S. history. Although improvements in some aspects of the crisis were starting to be realized as a result of the development of best evidence-based practice guidelines and the implementation of regulatory mandates for prescribing and monitoring treatment response, we were a long way from achieving our goal; to provide optimum care and improve quality of life for those in pain without causing harm to the patients, the healthcare system or society as a whole.

In many cases, the strides that had been made in mitigating the opioid crisis did not come without their own problems. The change of assessment, prescribing and monitoring standards imposed an unacceptable burden on many well-meaning physicians, who wished to help without harming their patients, but realized that compensation for the time necessary to comply with essential regulatory demands was inadequate. Because compensation issues were accompanied by fear of reprisal for non-compliance, many chose not to provide care for their patients’ pain problems, thus limiting patients’ options for identifying resources for appropriate evaluation and management of ongoing and persistent problems or for complications associated with previous inappropriate misuse, abuse or prescribing of treatments. The resulting uncertainty of care set the stage for frustration, stress, anxiety, anger and depression, each confounding factors in the management of uncontrolled pain.  

If addressing these options weren’t enough of a challenge, a new crisis, “the 2019-nCoV virus (COVID-19) pandemic” emerged in the population. The virulence of the virus, the uncertainty about its course and management, the frustration, stress and depression associated with individual isolation and distancing and the additional limitations on access to proper evaluation, delays in initiating possible condition-limiting treatment, follow up and monitoring of patients requiring controlled medications acutely added to the already present confounding factors that have hindered optimal recovery from the opioid crisis for both patients and practitioners alike.

Unfortunately, the distribution of promising new vaccines and potential control of the current pandemic may not completely eliminate the negative influence that the virus has had on delivering pain care. We are learning that a significant number of individuals, the “long-haulers,” who have survived a COVID-19 infection report experiencing persistent cardiac, pulmonary, renal, psychologic and neurologic problems consistent with direct or indirect multisystem injury as a result of the virus. The distribution and mechanism of injury producing the pain is unknown and likely multifactorial, but presentations are frequently multifocal and possess features of nociceptive and neuropathic pain with a hint of psychogenic quality consistent with organic central and/or peripheral nervous system involvement and the influence of post-traumatic psychosocial stress associated with contracting and fighting the disease. Optimal management of these complex pain problems will likely require a return to the basics promoted by John Bonica and others, that of a comprehensive and multimodal evaluation and the orchestration of pharmacologic, interventional, physical and psychological treatment modalities at all levels of the healthcare system.

As incoming president of the Southern Pain Society, I look forward to–and encourage others to work with me to — learn from healthcare providers and basic and clinical scientists from all specialties to improve and refine assessment skills, to identify viable treatment options and management planning and to provide continued education for clinicians in practice and those new to the field, in the hope of optimizing the quality of life for patients in pain.

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