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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.

Case Sample: Bipolar, Chronic Migraine, Epilepsy, and IBS-D

Lawrence Robbins, MD

Individuals suffering from chronic pain often have psychiatric comorbidities. For instance, among those with chronic migraine approximately 9% fit into the bipolar spectrum. (1) This article discusses a representative case of a patient with chronic migraine and bipolar disorder as well as epilepsy and irritable bowel syndrome.

Caitlin is a 28-year-old female who has experienced frequent depressive states since age 14. Caitlin finally was diagnosed at age 26 to be on the mild end of the bipolar spectrum (DSM-5: Other Specified Bipolar and Related Disorder: 296.89). She presents with her depression in remission. She is on quetiapine 50mg and 100mg of lamotrigine, each once per day.  

The patient has moderate chronic migraine and describes daily mild to moderate daily headache. She has a moderate migraine twice weekly, and a severe migraine attack once a month. She takes 8 OTC aspirin/acetaminophen/caffeine tablets (Excedrin) daily.

Caitlin reports significant occipital and neck pain. She has had tonic-clonic epilepsy since age 12. Her seizures are infrequent, and since being placed on lamotrigine she has had no further seizures. Caitlin also has moderate irritable bowel syndrome, primarily with diarrhea (IBS-D).

Work-up as negative, including MRI of her brain, routine blood tests (including thyroid), and the neurology examination.

What Additional History May be Helpful?

In this case scenario, relevant factors to consider and further investigate include:

  • Frequency and severity of the patient’s headaches
  • the past response to medications and family history of response (family history of medication response brings in the “placebo by proxy” and “nocebo by proxy” responses)
  • Potential sensitivities or side effects to medications
  • Psychiatric comorbidities
  • Medical comorbidities
  • GI issues (in this case, IBS-D)
  • Any complaints related to sleep, fatigue, or insomnia
  • The patient’s job requirements, social support, and any financial/insurance concerns that may impact her treatment
  • Patient preference for medication (eg, they may not wish to take daily medication, or may request to use natural remedies)

In addition, a history of the specifics of this patient’s depression would be helpful. The details of her moods, hypomanic symptoms, triggers, etc. are important if an adjustment to psychiatric medication is appropriate. (2)

Is the Patient Suffering from Medication Overuse Headache?

It is also worth considering whether the patient may have medication overuse headache (MOH) which is often conflated with medication overuse (MO). Medication overuse is arbitrarily viewed as consuming certain abortive medications (eg. combination analgesics, triptans, opioids, butalbital compounds) at least 11 days per month. If patients simply take NSAIDS, MO is defined as consuming the NSAIDS at least 15 days per month.

A determination of MOH is more complex as it tends to be poorly defined and over-diagnosed. (3) To determine if MOH is present, a careful history has to be taken as to the effect the drug had on the person’s headaches. The drug (in this case, Excedrin) must be withdrawn to see if the headaches improve. Caitlin reports taking 8 Excedrin on a daily basis, each of which contains 65 mg of caffeine. It would be helpful to determine how much additional caffeine she consumes.

We should attempt to limit her caffeine intake to 150 or 200 mg daily. While small amounts of caffeine help many patients, other migraineurs cannot tolerate even minimal amounts. 

To read the rest of this article, please click here

https://pro.psycom.net/psychopharmacology/case-bipolar-migraine-epilepsy

In Memory and Appreciation: Dr. John Satterthwaite

Ann Quinlan-Colwell, PhD, APN

It is with deep sadness that we recognize the life and contributions of  John Satterthwaite, MD who transitioned from this earthly world last month.  John’s perspective on the history and devotion to the mission of SPS were priceless. Many have no doubt that the SPS would not exist today it were not for the careful nurturing and stewardship of John during the last 34 years.  During those years, like the captain of a beloved ship he steered and guided SPS as he served as treasurer and  historian. 

As important as his contribution in those roles, John was so much more to many of us in the SPS.  Through his teaching, mentoring, guidance, and voice of reason, he significantly impacted numerous SPS members in ways that can never be repaid.  Not only was John a man of many talents who contributed greatly to the world of pain management but he had paradoxical qualities as well.  Although he was often a wise sage when on the stage, he was equally comfortable and meaningful being the guide on the side.  He was often a man of few words yet a great storyteller with an amazing sense of humor..

John was an expert physician, teacher, patriarch, sage, guide, shepherd, steward, mentor, storyteller,  navigator, voice of reason, friend, and so much more. You will be greatly missed, our dear friend.

An Essay on Diversity in the Field of Pain Medicine

Benjamin Johnson, MD

I would like to thank our president, Ann Quinlan-Colwell, PhD, APN, for the invitation to write an article regarding diversity in our field of pain medicine.  As the first president of the Southern Pain Society possessing African-American heritage, I was overwhelmed with the sage advice and enthusiastic support that I received from the “parents” of the Southern Pain Society, Hugh and Renee Rosomoff, as well as the board of directors and past presidents during my term of office.   In this brief article, I will address the issue of diversity in pain medicine in two parts: first, my own personal experience; and then offer some strategies to consider for the purpose of increasing diversity in the field of pain medicine.

My own introduction to medicine began with my family physician; and accelerated when I began to work as an electronmicroscopist with a Polish nephrologist in Chicago, Dr. Robert Muercke, who pioneered the percutaneous renal biopsy in the US.  While teaching me to interpret renal histopathology from his percutaneous renal biopsies, he encouraged me to pursue a career in medicine; and his letters of recommendation were instrumental in helping me to gain admission into the University of Illinois College of Medicine.

My first experience with blatant racism occurred during the process of applying for admission into medical school.   My undergraduate college (0.5% black enrollment) declined to write a letter of recommendation (the dean’s letter) for me to the medical schools, stating that they were afraid that I would adversely affect their percentage of successful admissions to medical school if I did not gain admission. 

My next major experience with overt racism came during my general surgery residency.  As a medical student, I had received high ratings in my advanced surgical rotations, and was strongly encouraged to pursue a career in general surgery.   I enrolled into a University of Illinois affiliated program that had a pyramidal structure. There were eight residents during the first two years of the program, and then only four residents were chosen to complete the last two years of the residency.  In my class, the eight residents consisted of four white males, one white female, and three black males.  At the end of two years, the four white males were chosen to complete the final years.  At this point, I interviewed with the Navy and applied for an anesthesiology residency at the Navy Hospital – San Diego.  While considering this move with my family, I was contacted by the general surgery residency director, who wanted to know if I was interested in re-joining the surgery program.  I suspected that the parent program had notified them that their resident selection results were somewhat suspect.  I decided to accept the anesthesiology residency program position with the Navy, which turned out to be one of the best decisions of my professional life. 

Regarding my experience in the noble field of pain medicine, I have been blessed to come in contact with several mentors of color, who have been instrumental in shaping my career. Dr. Winston Parris and the late Dr. Richard Payne are two mentors whose influence on me has been especially noteworthy.  Their involvement in the field of pain medicine since the Bonica era gave them a unique perspective, which they were eager to share with me. They gave freely of their knowledge, expertise and wisdom in both academic and private practice environments.  Due to their example, inspiration and encouragement, I have had the privilege to influence and mentor other physicians of diverse cultures and nationalities, including my African-American colleagues, in the wonderful field of pain medicine.  Additional mentors of diverse backgrounds, such as Gabor Racz, Prithi Raj, Claudio Feler and others have welcomed me into their practices to share their priceless wisdom and experience. This level of mentorship is crucial for the purpose of attracting diversity into our noble profession. 

Our president, Dr. Ann Quinlan-Colwell, asked me to address the question of what we as providers can do to increase diversity of our specialized field of pain medicine.   This is a complex issue, but I will offer some possible practical strategies for us to consider.  I will approach this subject from a broad perspective, and then offer some more specific concepts.

Before addressing possible strategies to increase diversity in our field of pain medicine, I would like to try to define a term that is often used when discussing the issues of diversity and disparity, that is the term “systemic racism”.  One sociological definition, by Eduardo Bonilla-Silva is the reference to systems in place that perpetuate racial injustice.  As defined, systemic racism has three primary components:

  1. Historic specificity: the systems adapt to changing conditions to maintain the disenfranchisement of a group of people
  2. A distinct structural phenomenon: the practices and behaviors are “baked” into the system itself; therefore the people in the system are consciously or unconsciously an essential part of the system. Regardless of intention, most people participate in some way, usually by being either passive or neutral.
  3. The system provides advantages for some, and disadvantages for others.

In view of this definition, the answer to solving a systemic problem involves a systemic solution. 

The effects of systemic racism occur in some of our most fundamental structures:

  1. Where you live
  2. What kind of education you’re able to receive
  3. How or if your family acquires wealth
  4. The quality of healthcare you can easily access
  5. How likely it is to face violent and deadly policing
  6. Your access to voting
  7. Where you worship

As we can see from the above definition, the issue of increasing diversity in the field of medicine, specifically pain medicine is only a part of a very large and systemic challenge.  In the next section, I will attempt to suggest how we as individuals can be a part of the solution, as opposed to being an unconscious participant in the problem.

Although I realize that the field of pain medicine is perhaps the best example of a truly multi-disciplinary field of healthcare, I will use the field of medicine as an example, since I know it best.  A number of years ago, I attended a meeting hosted by the Association of American Medical Colleges (AAMC), which dealt with determining strategies of increasing diversity in medical schools.  One of the key points brought out at this summit meeting was that the pipeline for medical school begins in pre-school, if not in utero.  Factors such as maternal health and nutrition, the quality of elementary and undergraduate education, and other socioeconomic conditions all weigh heavily on an individual’s ability to gain entry into medical school.  Potential physicians fall out of this pipeline anywhere along the pathway, as the above-mentioned variables adversely affect them.  Factors such as poor nutrition, dysfunctional families, substandard housing, poorly funded education, and economic deprivation, many of which are the result of systemic racism, all reduce the viable pool of physician candidates.  Therefore, the field of pain medicine is adversely affected as well. Although I’m using medicine as an example, other components of our multidisciplinary specialty, such as psychology, nursing, pharmacology, and others all suffer in similar manner.

What can we as citizens in this country do about such a pervasive and multifactorial problem?

First, it is important to be politically knowledgeable and active. 

Even though we are all busy practitioners with demanding, high stress positions, we must remember that we are still functioning members of society.  In a democratic society, we must be active participants in order to be agents of change. As an example, I used to be a volunteer anesthesiologist in the Philippines for a medical group called Operation Smile.  On several trips, I had the pleasure of working with some politically active women on the island of Negros Occidental.  I found out that they were so influential in their local communities, that if they backed a political candidate, the other candidates might as well give up!  It is this kind of political influence that can make a difference in our communities and nation.  We can accomplish this through our local civic organizations, churches, and other areas of influence.  Although the results of political activity are not always instant or readily observable, the long-term effects can be substantial. One of the things that I admire about the American Society of Interventional Pain Physicians (ASIPP) is their emphasis on political activity.  On an annual basis, member pain physicians have travelled to our nation’s capital to speak personally with our senators and members of Congress and inform them of how their legislative activity affects us as providers, as well as the patients who put their well-being into our hands. 

More specifically, what we can do as individual providers is to be role models and mentors to young potential pain medicine providers of diverse backgrounds and cultures.  Such activities as local career fairs, school classroom activities, medical student mentoring, and hosting of medical students or pain fellows in our practices can inspire our youth to enter our chosen field.  I know from experience that such activities can interfere with a practice’s operational efficiency; but it is a meaningful contribution to our communities and career specialties.  An added value is that such activities help to ameliorate the stigma that a pain practice can have in the community.  I have personally participated in each of the above-listed activities, and I can say without hesitation that having an individual thank you for inspiring them into a fulfilling career can really brighten your day.  I am a direct beneficiary of scientists who allowed me to work in their laboratories during my summers in high school, which introduced me to the field of electronmicroscopy and subsequently into medicine.  An additional benefit is the positive affirmation of pain medicine as a legitimate specialty within our communities.  These activities can also bring in new patients without spending marketing dollars.

I trust that this brief article has introduced you to some of the challenges in regard to creating diversity in our wonderful and fulfilling field of pain medicine.  Hopefully, we will have some stimulating discussions on these topics in the future.  My hope is that we can all be agents of change in our spheres of influence.

Transitioning from 2020 to 2021 – “The Times They are a Changing”

Ann Quinlan-Colwell, PhD, APN

For most of us, this past year has been tumultuous to say the least.  In at least some way, we have all been impacted by the COVID-19 pandemic, protests and the underlying circumstances that initiated them.  We are very fortunate that Dr. Ben Johnson wrote a thoughtful and insightful article in this issue regarding diversity in health care and with pain management in particular.  Every day, I learn about yet another way the pandemic has affected people and health care.  Many of our colleagues are reporting “Post COVID Stress Disorder” (PCSD).   Health care providers are struggling to maintain practices using virtual telehealth where possible.  Some have had to curtail performing “non-essential” analgesic procedures due to required personal protective equipment not being available.  Advanced practice nurses have been re-assigned from pain management to work in critically low staffing areas caring for patients acutely ill with COVID-19.  Still others have effectively been told that pain management is “not an essential service and in the interest of being financially responsible we are eliminating your position.”

Clearly, we are yet to witness the immense impact of chronic illness experienced by the COVID survivors who are being referred to as “the long haulers.”  This population will be particularly challenging since many of them have underlying co-morbidities or risk factors that are painful or increase the risk of experiencing pain. Many who have suffered pulmonary damage and complications will be at increase risk for medication related respiratory depression.  Since many people who have had COVID-19 reported neurological symptoms, we can hypothesize that neuropathic pain may be a long term consequence.  We are beginning to see literature discussing managing chronic pain during the pandemic  (Cohen, et al, 2020; Eccleston, et al, 2020; El-Tallawy, et al, 2020; Manchikanti, Kosanovic, & Vanaparthy, 2020;  Morgan & Dattani, 2020; Pradère, et al, 2020; Puntillo, et al, 2020; Soin & Manchikanti, 2020; Song, et al, 2020; Shanthanna, et al, 2020).

It is most certainly a time to amass resources to adjust our perspectives and our usual ways of functioning.  The more proactive we can be, the more internal resources we will have to best support people living with pain who are most certainly struggling. Functioning from a scientific perspective, garnering the evidence and supportive literature is basic (see reference list).  During this time with a certain degree of social and even professional isolation, it is also important to remain connected with other professionals.  The Southern Pain Society provides an excellent platform for doing so.  In addition to this newsletter, on November 13th and 14th we are scheduled to share amazing information during part one of our first ever Southern Pain Society Virtual Meeting.  The timely title of the meeting is: “Perspectives, Concerns and Options for Managing Pain” with presentations by a variety of internationally known faculty including Drs. Rollin Gallagher, George Singletary, Perry Fine, Jay Kaplan, Esther Bernhofer, and Misha Backonja.  We certainly hope to connect with you virtually to learn from these pain management professionals.

In addition, we have a special group of professionals serving on the SPS board of directors who work throughout the year to support information and education about pain management.  With annual regularity, the board composition is preparing to change.  As they step down from their board positions, we extend great appreciation to past president Mordi Potash, MD and director Joe Tramontana, PhD for their years of dedicated service.  During the next year, Dr. Harry Gould, III will assume the role of SPS president as I transition to past president and our long time treasurer Dr. Thomas Davis will become president elect.  We are thrilled that Drs. David Gavel and James McAbee will continue as directors and Dr. Randy Roig will continue as treasurer while Dr. James Weisberg will assume the role of secretary.  We are most pleased to welcome Drs. Michele Simoneaux and Eric Royster as new board members.  Without a doubt, this SPS board will work cohesively to continue to advance research and treatment of pain while increasing the knowledge and skill of all those in our professional community as we hopefully experience the end of the COVID-19 pandemic and move forward.  During this transition period, I encourage all to do everything possible to be safe and remain well.

References:

Cohen, S. P., Baber, Z. B., Buvanendran, A., McLean, L. T. C., Chen, Y., Hooten, W. M., … & King, L. T. C. (2020). Pain management best practices from multispecialty organizations during the COVID-19 pandemic and public health crises. Pain Medicine.

Dylan, B., & Sears, J. (1964). The times they are a-changin’ (Vol. 8905). Columbia.

Eccleston, C., Blyth, F. M., Dear, B. F., Fisher, E. A., Keefe, F. J., Lynch, M. E., … & de C Williams, A. C. (2020). Managing patients with chronic pain during the COVID-19 outbreak: considerations for the rapid introduction of remotely supported (eHealth) pain management services. Pain161(5), 889.

El-Tallawy, S. N., Nalamasu, R., Pergolizzi, J. V., & Gharibo, C. (2020). Pain Management During the COVID-19 Pandemic. Pain and therapy, 1-14.

Fauci, A. S., Lane, H. C., & Redfield, R. R. (2020). Covid-19—navigating the uncharted.

Gates, B. (2020). Responding to Covid-19—a once-in-a-century pandemic?. New England Journal of Medicine382(18), 1677-1679.

Manchikanti, L., Kosanovic, R., , & Vanaparthy, R.,  (2020). Steroid distancing in interventional pain management during COVID-19 and beyond: Safe, effective and practical approach. Pain Physician23, S319-S350.

Morgan, C., & Dattani, R. (2020). Should I use steroid injections to treat shoulder pain during the COVID-19 pandemic?. JSES international.

Pradère, B., Ploussard, G., Catto, J. W., Rouprêt, M., & Misrai, V. (2020). The Use of Nonsteroidal Anti-inflammatory Drugs in Urological Practice in the COVID-19 Era: Is “Safe Better than Sorry”?. European Urology.

Puntillo, F., Giglio, M., Brienza, N., Viswanath, O., Urits, I., Kaye, A. D., … & Varrassi, G. (2020). Impact of COVID-19 pandemic on chronic pain management: Looking for the best way to deliver care. Best Practice & Research Clinical Anaesthesiology.

Soin, A. & Manchikanti, L. (2020). The effect of COVID-19 on interventional pain management practices: A physician burnout survey. Pain Physician23, S271-S282.

Song, X. J., Xiong, D. L., Wang, Z. Y., Yang, D., Zhou, L., & Li, R. C. (2020). Pain management during the COVID-19 pandemic in China: Lessons learned. Pain Medicine21(7), 1319-1323.

Shanthanna, H., Strand, N. H., Provenzano, D. A., Lobo, C. A., Eldabe, S., Bhatia, A., … & Narouze, S. (2020). Caring for patients with pain during the COVID‐19 pandemic: consensus recommendations from an international expert panel. Anaesthesia.

Casey A. Murphy, MD Receives Award

John R. Satterthwaite, MD

Dr. Hu Rosomoff, the founding President of SPS, would take any opportunity to speak during each Annual and Board meeting until his health prevented him from attending.  Hu was a veritable fountain of clinical wisdom, as well as a provider of historical perspective into the Society.  Now, as the “Old Guy” from the Board I would like to exercise my “Rosomoff privilege” to briefly walk down memory lane.

I began in private practice of anesthesiology in Greenville, SC in 1980, not even knowing what pain management was. At the request of a local surgeon I began using injections, primarily epidurals, to treat pain in about 1983. At that time, only 2 or 3 pain fellowships existed.  Wanting to learn more about the treatment of pain and what others were doing, I began going to meetings and joined SPS in 1987 as a Charter Member after attending the combined ASP and SPS meetings. Yes, we had joint meetings in those days.

These meetings and interactions with leaders in the field like Dr. Rosomoff, Marty Grabois, John Loeser, and multiple others helped me expand my knowledge base and clinical skills. Historically at that time, use of opioids was frowned upon, functional restoration was encouraged, surgery and injections were not that popular, and off label medication use was common, leading to many currently acceptable treatments for pain problems today.

I was asked to become SPS Treasurer in 1989, a position on the Board which I held until 2019 when I was forced to retire, due to pulmonary fibrosis. During my time on the Board, I had the honor and privilege to work closely with many of the top names in the field of pain.  I will not try to name them all because I am sure I would leave some out.  Suffice it to say, their names would be familiar to all. In those 30 years, many young practitioners came to our meetings, became excited, joined, and were encouraged to become more active in the Society. In fact, all of the current Board members and officers became involved in this way.

Why is this important?

It is the role of the Society to recruit, teach, support, and mentor young clinicians to blossom and become the future leaders in the field of pain management. It is up to us as a Society to develop, teach, and maintain high standards of practice for the care and protection of our patients.  We must nurture and encourage these young people to carry on and lead us through the turbulent times of the 21st Century. 

I am quite humbled that the Society has named this Early Career Award for me.  This award recognizes young clinicians who have shown excellence in leadership, education, and research in the field of pain.  They are our future. 

I am honored to be able to present this first John R. Satterthwaite, MD Early Career Award to Casey A. Murphy, MD

Dr. Murphy completed his training at Louisiana State University, finishing medical school in 2013, followed by a PM&R residency and Pain Medicine Fellowship, finishing in 2018. He was inducted into AOA Honor Medical Society and is a member of multiple professional societies, including SPS.

He is on the faculty at LSU and Tulane and is a staff physician at the VA in New Orleans. He serves as the Program Director of the LSU Pain Medicine Fellowship, this only 2 years after completing his own fellowship training. He  has completed numerous research projects and studies, some of which have been presented at SPS meetings. He has developed a special interest in the medical management of cancer pain and continues to pursue this project to completion.

In addition to teaching and mentoring trainees, speaking, pursuing his research, and running a department, Dr, Murphy still finds time to spend with his wife Sarah and his two young children in New Orleans.

You can see by his history how dedicated he has been in the past 7 years since medical school. It is my honor to present this first annual award to Dr. Casey A. Murphy.

President Elect : American Society of Clinical Hypnosis

A member of our Board of Directors, Dr. Joseph Tramontana, a Clinical Psychologist, has been nominated and is running un-opposed for the position of President-elect of the American Society of Clinical Hypnosis (ASCH). His term will begin March 2021 and will transition to President in March 2022. ASCH is one of the oldest and most prestigious hypnosis societies in the world, originally founded by Milton Erickson, its first President. Annual conferences include international attendees, as well as international speakers.

Dr. Tramontana previously served as President of the New Orleans Society of Clinical Hypnosis (NOSCH), which is a component society to ASCH, for 5 years (2012-2017) and was Secretary of ASCH in 2017-18. He was also President of the Louisiana Psychological Association in 2014 and served on their Board for several years. He has published two books on hypnosis. The first was titled Hypnotically Enhanced Treatment for Addictions: Alcohol abuse, drug abuse, gambling, weight control and smoking cessation published by Crown House in 2009. The second titled Sports Hypnosis in Practice: Strategies, Scripts, and Case Examples was also published by Crown House (2011). A third book, titled Golf Peak Performance through Self-Hypnosis Training is currently in editing. This latter book is written for the golfer, not the treatment provider as were the first two. In addition, he teaches a “Hypnotherapy” course to Advance Psychology graduate students at the Chicago School of Professional Psychology’s Xavier University of LA campus. 

Dr. Tramontana also belongs to the American Association of Pain Psychologists.  He works collaboratively part-time with clinicians at a pain clinic in Metairie, LA.  Although not an employee of that group, they often refer to him as their “Pain Psychologist” because he sees many patients who experience pain while working there. 

Chaos, Migraine, and Evolution

Lawrence Robbins, MD

 INTRODUCTION

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

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

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

CHAOS AND THE NERVOUS SYSTEM

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

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

CHAOS AND MIGRAINE

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

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

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

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

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

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

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

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

CHAOS AND EVOLUTION

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

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

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

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

 EVOLUTION AND MIGRAINE

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

CONCLUSION

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

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

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

                                                               REFERENCES

Bird, R. (2003). Chaos and Life: complexity and order in evolution and thought. NY,NY: Columbia University Press.

Cochran G, Harpending H (2009). The 10,000 Year Explosion: How civilization accelerated human evolution. NY,NY: Basic Books.

Dawkins,R.  (2016). The Selfish Gene. Oxford, UK: Oxford University Press.

Dussor G, Cao,Y-Q. (2016). TRPM8 and migraine. Headache, 56, 1406-1417.

Fagherazzi G, El Fatouhi D, Fournier A. (2019). Associations between migraine and type 2 diabetes in women: findings from the E3N cohort study. JAMA, 76, 257-263.

Fujisawa S, Yamada M, Nishiyama N, Ikegaya N. (2004). BDNF boosts spike fidelity in chaotic neural oscillations. Biophysics J, 86, 1820-1828.

Kee Z, Kodji X, Brain SD. (2018). The role of calcitonin gene related peptide (CGRP) in neurogenic vasodilation and its cardioprotective effects. Frontiers in Physiology, 9, 1249.

Kernick D. (2005). Migraine—new perspectives from chaos theory. Cephalalgia, 25, 561-566.

Korn H, Faure P. (2003). Is there chaos in the brain? C.R. Biologies, 326, 787-840.

Landau ID, Sompolinsky H. (2018). Coherent chaos in a recurrent neural network with structured connectivity. Computational Biology, Retrieved May 20, 2020 from https://doi.org/10.1371/journal.pcbi.1006309

Loder E. (2002). What is the evolutionary advantage of migraine? Cephalalgia, 22, 624-632.

McCann K, Yodzis P. (1994). Non-linear dynamics and population disappearances. The American Naturalist, 144, 873-879.

McKee, J (2000). The Riddled Chain: chance, coincidence, and chaos in human evolution. Piscataway,NJ: Rutgers University Press.

Milton K. (2000). Hunter-gatherer diets: a different perspective. The American Journal of Clinical Nutrition, 71, 665-667.

Nesse,RM. (2005). Maladaptation and natural selection. The Quarterly Review of Biology, 80, 62-70.

Nesse,RM. (2011). Ten questions for evolutionary studies of disease vulnerability. Evolution Applications, 4, 264-277.

Nesse,RM, Williams GC. (2012). Why We Get Sick: the new science of Darwinian medicine. New York, New York: Vintage Books.

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Schweighofer N, Doya K, et al. (2004). Chaos may enhance transmission in the inferior olive. Proceedings of the National Academy of Science, 101, 4655-4660.

Vigano A, Manica A, Di Piero V, Leonardi M. (2019). Did going north give us migraine? An evolutionary approach on understanding latitudinal differences in migraine epidemiology. Headache, 59, 632-634.

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President’s Column July, 2020–Virtual Annual Meeting

Ann Quinlan-Colwell, PhD, RNBC, DAAPM

Last year we began planning our 2020 Southern Pain Society meeting,  “Perspectives, Concerns and Options for Managing Pain.”  Little did anyone realize that national events of 2020 would necessitate many concerns and needs.  We have worked to change our perspective as we explored options for safely coordinating an exciting conference to share timely and innovative pain management information.  Interestingly, in numerology, 20 is related to service and teamwork.  There is no doubt that the conference planning committee definitely exhibited a double effort of service and teamwork as they planned, evaluated, re-planned, explored options, re-evaluated, and redesigned this conference.

It is my great pleasure to share with you that the 2020 SPS conference will continue with the agenda topics and speakers planned.  We will be using a virtual format starting on November 13 and 14 and re-connecting again next March 12 and 13.  The virtual option allows for us to schedule shorter days at different times to avoid “Virtual Fatigue.”

The amazing presenters will discuss managing chronic pain throughout the continuum using pharmacological and nonpharmacological interventions for all types of pain including musculoskeletal and neuropathic pain.   A variety of measures will be presented, ranging from spinal cord stimulators and intrathecal treatments discussed by Eric Royster, MD, to acupuncture and Chinese herbal medicine presented by Arnuad Versluys, MD.  George Singletary, MD will explore all the uses for buprenorphine and Todd Sitzman, MD shares the current pharmacological and interventional therapies for managing osteoarthritis of knees. Miroslav Backonja, MD will review new pharmacological options for managing neuropathic pain.  Jonathon Cole, PhD will examine the reciprocal relationship between sleep and pain and Perry Fine, MD will share the lessons learned and explore the current needs and future opportunities for palliative care. Cases will be presented in which some of these options will be explored.

From a more universal perspective Rollin Gallagher, MD will share with us the back story of the HHS Pain Task Force Report and Scott Fishman, MD will update those attending about the guidelines and regulations for opioid prescribing.  Esther Bernhofer, PhD will share the ethical perspective of really doing the right thing for patients living with pain.  In a very timely session, Jay Kaplan, MD will discuss burnout and resiliency.   We are planning to have our traditional poster session and vendor exhibits.

No one ever wants to postpone a visit to New Orleans and while we regret not being able to connect with you in person in NOLA we certainly look forward to sharing the conference with you virtually.  There truly is something for everyone.  An innovative and fun addition to the conference this year will be the option to take a Virtual Historical, Architectural Walking Tour of the French Quarter guided by our own Dr. Randy Roig.  It will definitely be educational, entertaining, and fun!

Please save the dates and plan to connect with us virtually in November and next March. Please check our website for dates, times and registration options.

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