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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.

Perlman R. (2013). Evolution and Medicine. Oxford, UK: Oxford University Press.

Pietrobon D, Moskowitz MA. (2014). Chaos and commotion in the wake of cortical spreading depression and spreading depolarizations. Nature Review Neuroscience, 15, 379-393.

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.

Vreeswijk C, Sompolinsky H. (1998). Chaos in neuronal networks with balanced excitatory and inhibitory activity. Science, 274, 1724-1726.

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.

Cluster Headaches and Treatment Update

Lawrence Robbins,M.D.*

Summary of cluster headache characteristics and update on abortive and preventive treatments.

Cluster headache is among the most severe pains known to mankind. It is characterized by excruciating, debilitating pain lasting from 15 to 180 minutes, or occasionally longer. The pain is usually located around or through one eye or on the temple. The series of cluster headaches usually lasts several weeks to several months, once or twice per year. Clusters may occur every other year, or even less frequently. Several of the following are usually present: lacrimation, nasal congestion, rhinorrhea, conjunctival injection, ptosis, miosis of the pupil, or forehead and facial sweating. Nausea, bradycardia and general perspiration also occur in many patients. Attacks usually recur on the same side of the head. Cluster headaches tend to occur more in spring and fall. There is usually no family history of cluster headache, but occasionally there is such a family history.

Specific Characteristics of Cluster Headaches

Males are afflicted more than females by a 2.5 to 1 ratio. The onset of the clusters is usually between the age of 20 and 45, but there are many cases of clusters in teenagers and occasionally clusters begin in the 50s or 60s and rarely in the 70s. Women tend to have an older age of onset for their cluster headaches than men. Occasionally a brief aura may occur. The prevalence is 0.4% of the population.

The pain of the cluster attack is extreme and starts very quickly, usually without an aura or a warning. Within minutes, it becomes very severe. Although the pain is usually located about the eye or temple, it may be more intense in the neck or facial areas. Although usually unilateral, the pain changes sides in 10% to 15% of patients—either during a cluster cycle or the next cycle may see pain on the opposite side. The pain itself is excruciating, described in various manners as sharp, stabbing—“like my eye is being pulled out” and occasionally, throbbing.

The length of attack varies, but 45 minutes is the average. Cluster patients usually experience one or two headaches per day, but this may increase to as many as seven per 24 hours or decrease to as little as one or two per week. They usually occur around the same time each day, with the time period 9 pm to 10 am being the most frequent. Approximately half of the patients awaken from sleep with the headaches.

Cluster cycles, except in the chronic variety, usually last 3 to 8 weeks and then stop until the next bout of clusters. The clusters occasionally last as little as several days, or as long as 5 months at which time we begin to think that they may have converted to the chronic cluster type. Ten percent of cluster patients have chronic clusters in which there is no break of at least six months between attacks. One or two bouts of the clusters per year is average for most patients. They may increase in frequency with only several months in between bouts or several years may elapse between attacks. When periodic clusters begin at older ages, the chance of conversion to chronic cluster becomes greater. The natural history of clusters is not known, but the tendency is for the cluster series to stop at a certain age. Many patients “lose” their clusters in the late 30s or 40s, particularly if they have had them for many years.

During the cluster series, over half of the patients are very sensitive to alcohol and most patients will have an attack triggered by ingestion of alcohol. The other ‘headache foods’ are less important, but avoiding MSG, aged cheeses and meats, and chocolate is prudent during the cluster series. MSG, in particular, seems to trigger a more sever cluster in some patients. Cluster patients may have their clusters after stress is over and occasionally excessive cold, heat, or bright light have been associated with the precipitation of a cluster. However, most cluster patients have very little control over the clusters, except with medication.

The typical episodic cluster series builds over one to two weeks and peaks for one to three weeks and then decreases. In the 10% of cluster patients with chronic clusters, periods of peaks and valleys with the headaches also occur but an extended break without any clusters is not present. Chronic clusters are not usually consistent throughout the year but tend to increase in certain seasons. In managing the clusters, we keep in mind the fact that the clusters build and then peak so that I often treat them with somewhat less medication—particularly corticosteroids—in the beginning of a cluster period. The natural history of clusters is unknown. However, it appears as if the more years a patient has them, the more likely they are to abate.

Non-Medication Treatment of Cluster Headache

Other than medication, very little is available for sufferers of cluster headache. The pain is too severe for relaxation methods and some patients state that biofeedback or relaxation may actually precipitate or increase a cluster. However, learning simple deep breathing techniques or relaxation methods does aid some patients in helping to curb the anticipation of the cluster attacks. Much anxiety is generated during the day when the patient knows that nighttime brings intense, excruciating pain.

Icing the area of pain may help, although sometimes heat will be more effective. Some patients let the shower run hot water on their cervical area, or they use a shower water massage apparatus to allow the hot water to run over their cervical or frontal area. Pressing over the temporal area with moderate pressure is occasionally helpful. Cluster patients usually feel better when moving about during an attack. They tend to be active (such as pacing) as opposed to the quiet sought by migraineurs.

Medications For Cluster Headache

For most patients, both abortive and preventive medications are helpful and only in a minority of situations do we simply use abortive medicines.

The abortive treatment for clusters is the same for episodic and for chronic cluster headaches. Since the headache is very intense from the beginning and the pain is severe and excruciating, medication to aid the attack must act quickly. Most cluster attacks last less than one hour, averaging about 45 minutes, and thus oral pain medication is only of limited value. However, in patients whose attacks do last for more than one hour, pain medications may be useful—particularly if the standard cluster abortives are not completely effective. Anti-emetics are also used for those patients with nausea, and the sedative effect of these is often helpful.

First-Line Cluster Abortive Medications

The first line abortive cluster medications are as follows:

  • Inhaled oxygen(higher flow rate is much more effective)
  • Sumatriptan injections(3mg and 6mg available)
  • Imitrex® (sumatriptan generic is available) or Zomig® (zolmitriptan) nasal spray

Oxygen. Oxygen is effective in approximately 70% of cluster headache patients. To obtain a small tank with a mask is relatively easy and not terribly expensive. The tanks are usually rented for one month. If feasible, most patients with cluster headaches should attempt to use oxygen for their attacks. The patient should be sitting with the body leaning slightly forward. A mask is used and 100% oxygen is inhaled at 12 to15 liters per minute. In healthy patients with no pulmonary problems, the oxygen may be inhaled for 15 to 20 minutes. A rebreather mask is helpful.

Sumatriptan Injections. Injectable sumatriptan (Imitrex®, Zembrace=3mg epi-pen device, or the generic: pre-filled syringes, vials(draw up in an insulin syringe), Stat dose system) is generally effective. Sumatriptan pills are more helpful for migraine than for cluster headache, but oral triptans are occasionally adequate. Many patients are reluctant to give themselves injections but, for those who are willing, injected sumatriptan is usually effective—often within minutes—and with a minimum of side effects. Oxygen may be used in conjunction with sumatriptan, and escape pain medication may also be utilized. The new gepants are not indicated for cluster, and generally take too long to become effective.

The dosage of sumatriptan is usually 3 to 6mg given subcutaneously at the onset of the cluster headache. A repeat dose may be given at least one hour after the first injection. Two 6mg injections, or 12mg, is the maximum recommended dosage per 24 hours. Sumatriptan is administered subcutaneously by the use of a convenient auto-injector device. Sumavel™ DosePro™ is a ‘needle-free’ sumatriptan injection.  While Sumavel is convenient, it still does sting, and may bruise quite a bit. Also, vials of sumatriptan are available for use with an insulin syringe. By using the vials, the dose may be titrated(some cluster patients only require 3 or 4mg).

Daily use of sumatriptan has not been studied extensively. Thus, until further studies are known, prudent use of sumatriptan would dictate that no more than six injections per week be taken for cluster headache (less for migraineurs).

The side effects of sumatriptan are generally less than those with dihydroergotamine (DHE). Transient pain at the site of injection is common, and ‘icing’ the injection site prior to use may decrease this burning pain. Other side effects include tingling sensations, disturbances of taste, heat flashers, and feelings of pressure or heaviness. Side effects tend to be short lasting. Chest symptoms, flushing, dizziness, and overall weakness may also occur. Minor transient increases in blood pressure have been seen. Nausea is relatively common. Sumatriptan should not be used in children, in pregnant women, in the presence of hepatic or renal impairment, or with cardiovascular disease. Patients over the age of 45 should be screened for cardiac risk factors. The frequent chest pressure that occurs is not usually felt to be of cardiac origin.

Sumatriptan or (Zomig)zolmitriptan nasal spray: while not as effective as the injection for cluster headache, the nasal spray is very convenient and many patients prefer this route of administration. We usually limit the sprays to two per day, but for cluster headaches we will occasionally utilize a third spray as well. Of the two nasal sprays, Zomig nasal spray 5mg is more effective than the sumatriptan spray.  There is a 2.5mg Zomig nasal spray available, but the vast majority use the 5mg spray. While not as rapidly effective as the injections, the nasal spray works faster than triptan tablets. Speed is essential in relieving cluster headache, yet occasionally patients prefer the oral triptans.

Second-Line Cluster Abortive Medications

Second line therapies include oral triptans, ergots and dihydroergotamine (DHE), Cambia, ketorolac nasal spray or injections, oral pain medications and intranasal lidocaine.

Oral Triptans. Any of the oral triptans may help, but are usually too slow for cluster headache. Sumatriptan 100mg is the most commonly used oral triptan. The two slow-acting triptans, frovatriptan and naratriptan, are not usually used acutely for clusters. Occasionally, these longer-acting triptans are utilized, mostly at night, to prevent nocturnal clusters.

Ergotamine Tartrate. Strong vasoconstrictors, the ergotamines have many limitations. Ease of administration (they are available as tablets) is a major advantage of the ergots. The frequent side effects of nausea and nervousness limit their use. In older patients, the risk of angina or an actual myocardial infarction restricts its use. The rebound headaches that occur in migraineurs do not seem to be as prevalent a problem in cluster headache patients. The primary ergotamine preparations are generic Cafergot® pills, suppositories and Ergomar® sublingual pills. Peripheral vascular disease or hypertension are contraindications. Ergotamines may exacerbate peptic ulcer disease. The effective dose of ergotamine varies widely among patients. Ergots may be combined with the use of oxygen and other abortive measures but not with triptans.

Ergomar. Tablets contain 2mg of ergotamine tartrate with no caffeine. The usual dose is one pill sublingually at the onset of the cluster attack. Ergomar may also be swallowed and this route may be just as effective as the sublingual method. This may be repeated once in one or more hours and limited to two pills per 24 hours. Nausea is a common side effect as is a bitter or “bad’ taste in the mouth. Nervousness is a frequent side effect, but less so than with Cafergot because there is no caffeine in Ergomar. Ergotamines need to be used with great caution in the presence of hypertension, peripheral vascular disease, or peptic ulcer disease. If chest symptoms occur, ergots should be discontinued.

Generic Cafergot (only generic available). Consists of 1mg of ergotamine tartrate and 100mg of caffeine. Cafergot pills are the most convenient but least effective of the ergots. Dosage is one or two pills at the onset of headache, repeated every two hours as needed, with a maximum of four per day and ten per week. Side effects are similar to the preceding Ergomar discussion, with nausea and nervousness being common. Because of the caffeine, anxiety or nervousness is more common with Cafergot pills than with Ergomar. The same precautions discussed above in the Ergomar section also apply to Cafergot.

Compounded Cafergot Suppositories (only compounded available). These are less convenient but much more effective than the pills. Cafergot suppositories contain 2 mg of ergotamine tartrate and 100 mg of caffeine. The primary side effects are nausea and anxiety. The initial dose is one third or one half of a suppository and then the dose is titrated up or down, depending on the patient’s response. The dose may be repeated after one hour, up to a maximum of two suppositories per day and five per week. Some patients find that as little as one fifth of a suppository is all that they require. Side effects of Cafergot suppositories are the same as those of Cafergot pills. Nausea and anxiety always are limiting factors in the use of ergots.

Compounded Cafergot PB suppositories (only compounded available). These are similar but more effective than plain Cafergot suppositories. Cafergot PB contains 2 mg of ergotamine tartrate, 100 mg of caffeine, 60 mg of sodium pentobarbital, and 0.25 mg of 1-alkaloids of belladonna. Dosage is the same as for the plain Cafergot suppositories. Side effects are decreased, with less nausea and nervousness. Sedation may be a problem, however.

Dihydroergotamine (DHE). This is different from the other ergots in that it is primarily a venoconstrictor rather than an arterial constrictor. Since 1945, there have been relatively few serious side effects reported. DHE is available as an intramuscular (IM) or subcutaneous (SQ) injection or as a nasal spray (Migranal®). The usual dose is 1 mg IM or SQ, or one spray in each nostril to be followed in 10 to 20 minutes by one further spray of Migranal in each nostril. Side effects tend to be minimal with DHE, but nausea, a heat or flushed sensation, nasal stuffiness from the spray, or leg cramps may occur. Occasionally, chest heaviness is also seen. While DHE is not as effective as sumatriptan for cluster headache, DHE at times is the best alternative in patients who may be at some risk for cardiac disease. However, if patients have major risk factors such as uncontrolled hypertension or have known atherosclerotic heart disease, then DHE must be avoided. The usual maximum is three injections per day or two nasal sprays in each nostril per day. A new inhaled form of DHE is expected to be approved shortly. The inhaled form will have better efficacy than the Migranal spray, but not as effective as the injections.

Cambia. Cambia is a powdered form of diclofenac potassium, 50mg. Cambia is FDA approved for migraine. The usual dose is 1 packet(with water, or apple juice) every 2 or 3 hours as needed. GI side effects may limit use. Cambia may be combined with a triptan. Cambia has a quicker onset of action than tablets of nsaids.

Ketorolac nasal spray(Sprix) or ketorolac injections. Sprix is a nasal spray of ketorolac, faster acting than tablets but not as powerful as the injections. Sprix is relatively well tolerated; the usual side effects include a feeling of burning in the throat, and GI side effects.  The ketorolac injections, 30 or 60mg, are effective for many migraine and cluster sufferers.  GI and renal concerns limit use with ketorolac. Ketorolac should be limited to 6 doses per week. s

The abortive analgesic medications include, among others,  the following;

  • Extra Strength Excedrin®
  • Butalbital compounds (Fiorinal®, Fioricet, Esgic®, Phrenilin: all are available as generic)
  • Opioids

In general, we do not want to have cluster patients rely on butalbital or opioids. However, in some refractory patients the pain is so severe and the other therapies are ineffective, justifying the use of butalbital or opioids.  The milder approaches, such as Excedrin, should be utilized first, then the butalbital compounds or opioids. While rebound or withdrawal headache is less of a concern with cluster than migraine, we still must try and limit the abortives. At times, this is not an easy task.

Lidocaine spray.  There are various devices for SPG blocks(Tian360, Sphenocath) used as a 4% lidocaine solution, the spray has been used since the mid-1980s for cluster headache. I have found it only mildly effective for most patients and almost never adequate by itself. However, intranasal lidocaine does provide sufficient relief to warrant its use. Lidocaine is very safe,  with minimal side effects. When used in conjunction with ice and one of the first-line abortives, the lidocaine spray may add 10 to 30% relief.

I put 4% topical lidocaine in a plastic nasal spray bottle. The patient is then instructed to lie in the supine position, extend their head back 30 to 45 degrees, turn the head toward the side of the pain and spray two or three sprays of the lidocaine intranasally. This may be repeated, but I usually limit the lidocaine sprays to six or eight in a 24-hour period. If the nasal passage is blocked, several drops of 0.5% phenylephrine may be used prior to the lidocaine.

Alternatively to the spray bottle, 1 ml of 4% topical lidocaine may be slowly dropped, via a dropper, into the nostril on the side of the pain. Side effects are minimal and may include numbness in the throat or, rarely, nervousness or tachycardia.

Another option for home use is to utilize a TB syringe, with lidocaine, and an atomizer. This is inexpensive.

Preventive Medications(see table 2)

Each cluster patient is unique, with a number of variables determining where we go with medications. If a patient has a short episodic cycle, we may just use abortives, or cortisone plus abortives.  For longer cycles we want to initiate one of the usual preventives, such as verapamil. Chronic cluster patients usually require daily medication for most of the year.  Most often, we use cortisone(usually Prednisone) for a short period of time, while initiating another preventive, such as verapamil.  Prednisone, while usually very effective,  should be limited; we want to minimize cortisone side effects. There is some evidence that cluster sufferers may be slightly more prone than others to femoral head necrosis from cortisone.

Comorbidities often determine where we go with medications. If a cluster sufferer is older, smokes, has HTN and reflux, we will be limited as to our medications.  Age, GI problems, psychiatric conditions, and previous reactions to medications all contribute to our medication decisions. For those with chronic clusters, we want to utilize medications that have minimal long-term side effects.  Table 2 summarizes the usual preventive approaches to preventing cluster headaches.  For quick relief, occipital injections with bupivicaine and/or cortisone may be effective. Frontally, the SPG blocks, with bupivicaine, often are helpful for frontal chronic migraine, and cluster headache. They are done via the newer Tx360 device, or the SphenoCath device. SPG blocks, with one of these devices, are very safe, and only take minutes to administer.

Refractory Clusters: For those cluster sufferers who have not found relief with the usual ministrations, a number of approaches have been utilized.  Emgality, a monoclonal antibody used for migraine prevention, is now approved for episodic cluster(300mg once per month). Unfortunately, because of the small numbers in limited studies, evidence is lacking for many refractory approaches. These approaches include: stimulants(methylphenidate, mixed amphetamine salts), melatonin, testosterone, SPG blocks, daily opioids, daily triptans(used as a preventive), daily ergots(rarely used),  botulinum toxin, and psilocybin, among others.  There are several cluster headache support groups, such as Clusterbusters.  Clusterbusters runs an excellent annual meeting of cluster headache sufferers.

I have found daily triptans(usually 1 at nite, as a preventive) to be helpful for some patients. The longer-acting triptans, frovatriptan and naratriptan, are usually used for use on a daily basis.  SPG blocks are easy to administer with the newer devices(Tx360 and SphenoCath), and used 2 to 4 times weekly they can be very helpful.  For some refractory chronic clusters, the implantable ATI SPG stimulator may be very helpful;  this is being utilized at several centers in Europe, and studies are ongoing in the U.S.  As a last resort, opioids may at least alleviate some of the suffering.  Psilocybin(illegal in the U.S.; we cannot advocate its use) has had some research behind it, and has been helpful for some patient

 Sample Case History

Richard is a 40-year-old man with a history of 4-week long cycles of cluster headaches, occurring once a year in the fall. The headaches began when he was 35. The cluster period begins slowly, increasing over one week’s time and reaching a peak where Richard has 2 or 3 severe attacks per day. These occur during the night from 10 pm to 3 am. Each cluster attack lasts from 40 to 90 minutes, and the pain is severe. The headache is always on the right side, and is accompanied by eye tearing and nasal congestion.

Treatment Plan

Richard visits our office during the first week into his 4-week headache series. The headaches are increasing in intensity and he is miserable from the pain. At this point, we want to put Richard on a prophylactic regimen, and give him an abortive to help ease the acute attack. We decide to use prednisone, one 20-mg tablet in the morning and another with dinner (40 mg/day) for 4 days. We will reduce this to 20 mg/day after the first 4 days, and then to 10 mg/day after another 6 days. We will then taper off the prednisone entirely over the next 4 to 6 days.

Limiting the amount of corticosteroids is important for two reasons: 1) serious side effects are decreased, and 2) if necessary, we may want to utilize additional prednisone later in the cluster series. If the patient has been on a high-dose of steroids for 3 weeks, we cannot use more corticosteroid. In contrast, by keeping the amount to a minimum, we are able to use steroids later in the cluster period. Cluster sufferers may be more prone to femoral head necrosis with the use of corticosteroids.

With the prednisone, we begin a slow release form of verapamil. This is started at 240 mg/day; we may eventually increase to 2 doses per day, which is generally the maximum (480 mg/day). As the prednisone dose is decreased, and the patient is weaned off the medication, it is hoped that the verapamil will have taken effect.

The use of oxygen as an abortive is discussed with Richard, but he prefers to wait. We give him sumatriptan tablets, 100 mg, as he is reluctant to self-inject sumatriptan. Richard is also instructed to apply ice to the areas of pain. (See Table 2 for list of the most common preventative agents prescribed for cluster headaches.)

Results

Six days later, Richard calls the office. He has had 5 very good days, but as the prednisone is being decreased, the headaches are becoming more severe. Sumatriptan tablets do not help; last night, he had 90 minutes of extremely intense pain. At this point, we convince Richard to try oxygen, at 12 to 15 L/min, as needed, and he rents a tank. Richard also is given sumatriptan injections, 4 mg.

We continue the original plan of decreasing prednisone, and we increase the dose of verapamil to 480 mg/d. We will monitor Richard’s blood pressure. He now has oxygen and sumatriptan injections available as abortive agents; adding lithium or valproate are considerations, as is indomethacin.

I see Richard 4 days later. He is now in his third week of clusters, and by his previous pattern, has 1 to 2 weeks left in the cycle. However, at times a cluster period may exceed the previous one in length, and extended cluster periods of up to several months do occur. Richard states that the oxygen does help his headaches.

The clusters are less severe, but still occur regularly twice at night. Sumatriptan injections stop the attacks within 10 minutes of administration. The verapamil may be having some effect as well. He is down to 20 mg/day of prednisone, and we decide to taper off the dose over the next 4 days. If the headaches increase dramatically, he could return to the prednisone.

Six days later, the headaches are gone, and after a week without headaches, Richard is tapered off the verapamil over the course of 6 days. If the headaches were to return during those 6 days, we would immediately increase the dose of verapamil to the maximum of 480 mg, and consider using prednisone again.

Discussion

It is important to chart which medications are most effective for treating a patient’s cluster headaches, so as to be ready to use them for the next cluster series. I usually write the plan for the next series in the patient’s chart, and inform the patient of the plan.

In Richard’s case, we would use oxygen as an abortive, with injections of sumatriptan. As a preventive, he would be given verapamil, increasing to 480 mg/day, and approximately 2 weeks of prednisone. Instead of the injections, zolmitriptan(Zomig) nasal spray would be a consideration, and occipital nerve blocks are a reasonable possibility. SPG blocks are a strong consideration. Other preventives would include lithium, indomethacin, sodium valproate or topiramate.

Most patients with cluster headaches are prescribed both preventative and abortive therapies. Compared to migraine management, we have relatively few medications that are effective for the treatment of cluster headaches. In order to minimize the use of corticosteroids, it is important to initiate preventive medications early in the cluster cycle. For the typical episodic cluster cycle, we begin medication with the onset of the cluster, and discontinue all medication shortly after the cycle ends. There is no demonstrated utility in continuing medication after the episodic cycle ends.  NOTE: This is an updated version of a section from L.Robbins’s book, Advanced Headache Therapy. This discussion is not prescriptive; all medications have side effects, and should not be used without informed consent and a discussion between the patient and physician.

Table 1. Typical Characteristics of Patients with Cluster Headaches

  • Begins between ages 20 and 45, approximately 0.4% of the population
  • Male predominance in a 2.5 to 1 ratio
  • Same time of year with no headache in between the cluster cycles
  • Primarily nocturnal attacks (but may be anytime)
  • During cluster cycle, alcohol triggers the headaches
  • Severe, excruciating, unilateral pain—usually periorbital
  • Ipsilateral rhinorrhea, lacrimation, conjunctival hyperemia, sweating of the forehead, Homer’s syndrome

Table 2. Common Preventive Medications for Cluster Headaches

NOTE: Emgality, a monoclonal antibody used for migraine prevention, is now approved for the use of episodic cluster headache. The migraine dose is 120mg per month; the dose for clusters is 300mg once per month.

Class/Agent Dosage Side Effects Comments
Corticosteroid:

Prednisone

20 to 40 mg/d for 3 to 6 days, then taper off over 4 to 8 days. Corticosteroids have many adverse effects. When used for short periods of time, the most common side effects are insomnia, gastrointestinal (GI) upset, and anxiety. Serious adverse events have occurred with even short courses of corticosteroids. Very effective for cluster headache, cortisone is used primarily for episodic cluster headaches. It is given for 1 to 2 week duration during the peak of the cluster series. Additional cortisone may be given later in the cycle, when the cluster headaches increase. Higher doses may be needed when the cluster cycle is peaking in intensity. Due to adverse side effects, it is very important to minimize the use of cortisone.
Calcium Channel Blockers:

Verapamil ER

At onset of headache, 240 mg/d or bid—maximum dose 480 mg/d Constipation. Electrocardiogram (ECG) should be performed because of possible cardiac abnormalities when higher doses are used. Very effective in episodic and chronic cluster headaches. Often initiated at the onset of the headache, in conjunction with cortisone. Verapamil is then continued while the cortisone is tapered and then stopped. Because of its efficacy and minimal side effects, verapamil is a mainstay of cluster headache prevention.
Lithium 300 mg/d to 900 mg/d Well-tolerated at low doses; drowsiness, mood swings, nausea, tremor and diarrhea may occur. Helpful for chronic cluster, and to a lesser degree, episodic cluster headaches. It may be combined with verapamil and/or cortisone. Blood tests need to be performed to assess kidney and thyroid function
Non-steroidal Anti-inflammatory Agents (NSAIDS):

Indomethacin

Indomethacin: 25 mg once or bid; up to 75 mg bid or tid. GI side effects may limit use. Powerful NSAID, indomethacin can be helpful for some cluster headache patients.
Anti-Epileptic Agents:

Sodium Valproate

500 mg/d to 1500 mg/d

 

May cause weight gain, fatigue, and GI upset, among other side effects. Valproate and topiramate are occasionally effective against cluster headaches. They are the mainstay of treatment against migraines, but less effective against cluster headaches.
    Topiramate 50 mg/d to 200 mg/d Does not cause weight gain, but cognitive side effects may limit use.
Botulinum Toxin A Injection(only occasionally used)(off label for cluster headache; not as effective as for chronic migraine) 50 to 200 units Safe, usually no adverse effects; may cause eye droop, or (rarely) generalized weakness. Botulinum toxin type A FDA-approved for chronic migraine. While the injections are not as effective for cluster headaches, they do help in some patients.
Occipital Injection:

Corticosteroid

Triamcinolone: 20 to 40 mg

Other forms of injectable steroid have also been utilized.

Steroid injection: local site reaction, or systemic corticosteroid effects (see above). May decrease cluster headache occurrence for up to 4 weeks.
    Bupivacaine Bupivacaine: 2 to 5 mL) Bupivacaine: allergic reactions may occur (rare) May decrease cluster headache occurrence for up to 4 weeks.

Sphenopalatine Ganglion(unilateral on the side of the cluster)

Nerve Blocks(SPG Blocks)      Bupivicaine 0.5%   Bupivicaine              Serial(2 to 4X per week)

allergic rxn(rare)      blocks may be effective

Tx360 device  or SphenoCath(these are expensive); Or, the patient may do it at home, (VERY INEXPENSIVE) with a TB syringe and atomizer, with 4% lidocaine. We usually demonstrate it in the clinic for the first time. A plastic spray bottle, with lidocaine, may also be utilized.

 

* Lawrence Robbins is a headache specialist and neurologist north of Chicago. He is an assistant professor of neurology, CMS. Lrobb98@icloud.com

President’s Column: Living with Chronic Pain During the COVID-19 Pandemic

Ann Quinlan-Colwell, PhD, RNBC, DAAPM

During the last five years, the focus upon, and priority for effective management of pain have dramatically shifted.  After more than a decade of efforts to improve the awareness of pain and appreciate the need for pain management, health care system administrators and providers were keenly aware that pain management was an important health care need.  In addition, in 2013 they learned that the patient experience of care constituted 30% of the weight of value based purchasing (CMS, 2013).  At the same time, they realized that patient satisfaction with pain management was an important component of the general patient experience of care.  They also realized that patient satisfaction with pain management was an important component of the patient experience.  Pain was a strong focus of health care system administrators, clinicians.  Then in 2016, the opioid crisis emerged and served as a potent change agent.  The focus and attention of heath care system administrators and clinicians shifted from concern about patient satisfaction with pain to preventing opioid misuse and abuse.  It is not possible to know to what degree, on a visceral level the opioid crisis touched clinicians who had been taught to submerge their ophiophobic fears.  They now could quote support for not prescribing opioids or at least not as many opioids.  Although I have not done a literature comparison, it certainly seemed as time passed information about opioids and substance use disorder far supplanted information about pain in the literature during the last few years.  Then in 2019, two icons of pain management ceased to exist.  The loss of the American Pain Society and the Academy of Integrative Pain Management as sources of leadership, guidance and research were significant.  As we entered 2020, I was hopeful that we had suffered the worst blows to pain management.  Yet new challenges face us.

In January 2020, the 2019 novel coronavirus (COVD- 19) was reported in Lancet.  On the surface many may wonder what negative impact COVID-19 could have on people living with pain. Unfortunately, during this time the barriers that people living with pain face are bolstered and in some cases expanded.  Many people living with chronic pain have serious co-morbidities venturing outside their home is not recommended (Szalavitz, 2020). It is difficult to maintain a safe distance of 3 to 6 feet in community settings or stores.  As an example, last week, I was standing 6 feet behind a man in a supermarket who was 6 feet behind the person in front of him.  A late middle aged woman started to stand in front of me.  I explained that I was in line and maintaining safe space and social distancing.  She waved her hand and said “Whatever!”  She then proceeded not to respect space behind me.  She didn’t seem to understand or accept the concept of personal space and social distancing. Currently when it is necessary for people who live with pain to go outside for a clinician visit or to refill a prescription transportation options may be more limited, less safe or unavailable.  Some may feel they need to choose whether to comply with quarantines and go without pain medicine or break the quarantines to obtain the medicine (Szalavitz, 2020).

Last week, the following important information regarding opioid prescriptions during the COVID-19 pandemic was written by members of the Practical Pain Management Editorial Board (PPMEB, 2020): “with federal law superseding state law, and with the current coronavirus declared as a public health emergency, providers are in fact able to prescribe controlled substances, such as opioids, via telemedicine. The DEA’s Diversion Control Division has noted that, “For as long as the Secretary’s designation of a public emergency remains in effect, DEA-registered practitioners may issue prescriptions for controlled substances to patients for whom they have not conducted an in-person medical evaluation, provided the following conditions are met: The prescription is issued for a legitimate medical purpose by a practitioner acting in the usual course of his/her professional practice; The telemedicine communication is conducted using an audio-visual, real-time, two-way interactive communication system; and The practitioner is acting in accordance with applicable Federal and State laws.”   Additional information is available at www.deadiversion.usdoj.gov/coronavirus.html.

Other limitations are facing people living with pain who are trying to access integrative therapies which help them to manage pain. Physical therapy, massage, chiropractic, yoga, tai chi, water aerobics, swimming and fitness centers are not currently accessible in many communities.  Again, technology can be of help for some.  There are apps on smart phones and tablets that guide yoga and tai chi.  There are dance and exercise videos available as well. Certain out-patient physical therapy groups are guiding family members and patients via teleconferencing while some nurses are working with patients with relaxation techniques over the telephone or via teleconferencing.  For most people, living during this COVID 19 pandemic is a stressful time that can lead to sleep difficulty, anxiety and depression. For people living with pain, each of those can  make the perception of pain more intense and/or can make it more difficult to manage.  Similar to yoga and tai chi, there are many apps on electronic devices to facilitate relaxation and promote sleep.  Psychological oriented hot lines are available to support people with anxiety or depression.  Some clinicians are modifying their work to a teleconferencing mode. Recently the Centers for Medicare and Medicaid Services (CMS) expanded access to and coverage for telehealth care including virtual check-in and e-visits provided by clinicians including physicians, nurse practitioners, and licensed clinical psychologists (Drakulich, 2020).

CMS.gov table available at https://www.practicalpainmanagement.com/sites/default/files/imagecache/lightbox-large/images/2020/03/26/03.17.2020%20Summary%20of%20Medicare%20Telemedicine%20Services%20Chart.png

Continuing patient education is imperative for clinicians and for people living with pain to learn about the new modifications for opioid prescribing and the expanded telehealth options.  It is also important for them to learn that there are a number of scams alleging to be from Medicare and Social Security.  People living with pain may be vulnerable to these and need to know to be cautious.  One patient with a long history of mental health issues, responded to a spam and unwittingly surrendered her Medicare coverage and agreed to a very pricey private insurance that did not meet her needs.  Fortunately, a strong patient advocate was able to intervene and reverse the agreement.

There is no doubt that during 2020 patients living with pain will be challenged with stress and barriers.  As professionals there are ways that we can be supportive and helpful.  We may even find that by meeting the challenges of COVID-19 we will learn new options for helping and caring for people living with pain.  We may even find that they may be more effective.

References:

Centers for Medicare & Medicaid Services. (CMS).  (2013). Hospital Value-Based Purchasing. Available at http://www.qualitynet.org/dcs/ContentServer?cid=1228772237147&pagename=QnetPublic%2FPage%2FQnetTier3&c=Page.  Accessed 3/30/2020.

Drakulich, A. (2020).  Telemedicine in the Time of Coronavirus.  March 16, 2020.  Practical Pain Management.

Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., … & Cheng, Z. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet395(10223), 497-506.

Practical Pain Management Editorial Board. (PPMEB).   (2020).  Managing pain and related symptoms during coronavirus.  March 16, 2020.  Practical Pain Management.

Stephen, P. (2016). Study – Wilmington No. 1 in opioid abuse.  Star News.  https://www.starnewsonline.com/article/NC/20160421/NEWS/605049449/WM. Accessed 3/30/2020.

Szalavitz, M.  (2020). People who take opioid painkillers are getting skrewed thanks to coronavirus.  https://www.vice.com/en_us/article/z3b5nj/coronavirus-shows-just-how-cruel-our-drug-laws-are-for-pain-patients-and-methadone-users   Accessed: 3/30/2020.

COVID-19 and the SPS Annual Meeting

Lori H. Postal, RN, MHA

As COVID-19 continues to influence individual and corporate function worldwide, The Southern Pain Society leadership is working diligently to ensure the best plan for our upcoming Annual Meeting in September. We would like all to know that while information on the current unprecedented pandemic is evolving quickly, your health and safety remains our primary concern.  The SPS board is meeting virtually and regularly and is currently hopeful that the meeting can be held as scheduled and that you will attend. However, we are also preparing a variety of contingencies in the event that a change should be necessary.

As COVID-19 evolves and more information becomes available, we will keep you informed of updates and any further decisions through our website, social media platforms and emails.

Thank you for your membership, support and engagement as we work through this crisis.  Please take care of yourselves and your loved ones and especially those on the front-line caring for patients.

Determination of Adverse Effects In Clinical Trials

Lawrence Robbins,M.D.

The efficacy of new drugs is usually reasonably accurate. We have multiple scales for efficacy, and the studies are powered for clinical effect. However, the studies often produce inaccurate adverse event or adverse effect profiles. To determine the likely adverse effects, post-approval we have to piece together multiple lines of evidence. These include published studies, physician experience, the FDA/FAERS site reports, and patient experiences. The physician online chat boards have been very helpful in outlining common adverse effects. The moderated and controlled Facebook patient chat boards have also been somewhat useful. I have previously published on the adverse effects of the migraine monoclonal antibodies. We(myself and Brooke Phenicie,NP-C) recently published a “checklist of adverse effects” study involving the migraine monoclonal antibodies. (1,2,3). I report a brief summary of those results here.

Recap of Results and the Utility of a Checklist

Initially patients were asked about adverse effects, and then they were presented with a checklist. 79 of the 119 patients identified at least one additional adverse effect by use of a checklist. Many patients described multiple additional adverse effects. The majority of additional adverse effects were mild. This study demonstrates the value of a checklist of symptoms in the evaluation of adverse effects.

Monoclonal Antibodies for Migraine Prevention: The Acquisition of Adverse Effects

As of September 30, 2019, the U.S. Food and Drug Administration (FDA) Adverse Events Reporting System Dashboard lists 20,871 adverse events attributable to the 3 migraine monoclonal antibodies. 2,825 events were deemed serious, with some identified as life threatening. (4) Only a small proportion of actual adverse events are reported to the FDA. For only 1.3 years of use, these numbers are staggering. The FDA, as well as similar organizations in other countries, would do well to investigate these adverse events. Adverse events attributable to erenumab accounted for 16,215 (2,367 serious) of the total. Galcanezumab use resulted in 3,465 (284 serious) adverse events, while fremanezumab had 1,191 (178 serious) reports. (4) Erenumab was the initial mAb prescribed in the U.S., and is still the mAb most commonly utilized. This may be a primary reason for some of the discrepancy between erenumab and the other mAbs with regard to the number of reported adverse events. Over time we will be able to determine if one mAb truly carries an enhanced risk for adverse effects. These mAb numbers are significantly higher than those reported for onabotulinumtoxinA. OnabotulinumtoxinA only averages approximately 2,000 reports per year, with few serious issues (in the doses used for headache).
We have prescribed mAbs to over 1,200 patients and they have reported a multitude of adverse effects. Constipation (20% of patients in our study on erenumab, less among the other mAbs) is the most commonly reported AE. (5) At times the constipation is severe, greatly affecting quality of life. Other adverse effects across all 3 mAbs have included: worsening headache (6%), depression (4%), fatigue (4%), nausea (4%), joint pain (3%), and hair thinning or loss (3%). (2) We have encountered a serious adverse effect in 4 patients, including: 1. A 60-year-old woman who had an episode of reversible cerebral vasoconstriction syndrome, which resolved, 2. A 21-year-old woman with a history of hemiplegic migraine (none since 2015), on the birth control pill, who suffered a probable migraine-related stroke, with an 80% improvement over 5 months, 3. A 65-year-old woman, with a history of rheumatoid arthritis, who reported severe joint pains and fatigue, which resolved, and 4. A 31-year-old woman who suffered from severe neurologic symptoms, including hemiparesis. She also suffered from joint pain and fatigue. A complete work-up was negative, and she eventually fully recovered.
We have been in communication with many headache providers concerning their experience with the CGRP mAbs. Constipation is commonly described as an AE. The rate of constipation that these providers report varies between 10% and 80% of patients. Anecdotally, it appears that erenumab causes constipation at an increased rate over the other mAbs. One observational study concluded that adverse effects accounted for 33% of discontinuations from erenumab. (6) Most providers feel that the AEs in clinical practice outnumber those reported in the studies. There also are providers who have encountered very few adverse effects among their patients.

The CGRP monoclonal injections (primarily erenumab) were reviewed by Quarterwatch, a publication that evaluates new medications. They rely upon a number of sources, including post-approval studies and the FDA reports. Quarterwatch researchers cited the “sheer number of case reports.” They noted that a large number of patients had experienced adverse events. Constipation was the most prominent AE. Hair loss was also mentioned as generating a clear signal. (7)

Other AEs acknowledged by Quarterwatch included muscle cramps, muscle spasms, and arthralgias. Thirty-five cases of anaphylactic shock were recognized. Depression was also listed as a concern. They state that “depression warrants additional study.” The authors mentioned signals for cardiac events. These included arrhythmias, palpitations, tachycardia, and cardiac arrest. Cases of loss of consciousness were also described. (7)

Quarterwatch concludes that “….it is likely that adverse effects of this migraine preventive were underestimated in the clinical trials.” In addition, they state “…the long-term effects of blocking all the functions of a highly prevalent signaling molecule remain undetermined.”
Quarterwatch, in December 2019, reviewed the frequency with which adverse events are reported to the FDA. Quarterwatch estimates that, in general, only 1% of serious adverse effects are actually reported to the FDA. Side effects to generics are rarely reported. However, the newer branded biologics, such as the migraine mAbs, are reported more often. Still, there are many serious side effects to the mAbs that go unreported.

The patient online chat boards and support groups help to provide insight into “real world” experience. Many patients state that they have had excellent results, with no adverse effects. However, many adverse events are also described. I have reviewed 400 adverse effects that were felt to be credible. The most common AEs described online by patients include fatigue, constipation, hair loss, depression, anxiety, and nausea. Many patients attempt to discuss adverse effect with their physician, and often they are dismissed with phrases such as “That AE cannot be due to the drug. They are safe.”
The adverse effects that we gleaned from patient comments somewhat matches the AE profile reported in our previous studies. They are also similar to what is stated on the FDA Adverse Event Reporting Dashboard.

Interfering with the molecule CGRP carries a multitude of possible risks. Evolution has decided that CGRP is a vital compound throughout the body. CGRP plays an important role during stress. These compounds have not been studied under stressful conditions. The blood brain barrier does not protect certain key areas, such as portions of the hypothalamus and pituitary glands. (3) Studies of various hormones, particularly in younger patients, have not been published.

The Phase 2 and 3 mAb studies significantly underreported the adverse effects. There are a number of reasons as to why they missed the adverse effects. Thomas J. Moore (Senior scientist, Institute for Safe Medication Practices) outlined this in his chapter “Assessment and Reporting of Harm.” (8) There are myriad scales and methods for describing efficacy in trials. With regard to adverse events or effects the methods for evaluation are lacking. Trial subjects are usually healthier, with fewer psychiatric and medical issues, than the patients we encounter in our offices. As compared to our chronic migraineurs, most of the study patients have used fewer preventive medications. For most of the mAb studies patients were simply asked, during follow-up visits, if they had any new symptoms or issues. This method may identify many of the serious AEs, but usually underreports milder issues. Psychiatric AEs often are not volunteered by the patient. Study personnel ideally should have a checklist of likely side effects. Patients should be asked, during each visit, about the predetermined items on the list. Adverse effects differ regarding duration of effect, severity of the AE, and how often it has recurred. It would be best if each adverse effect would be categorized as “mild, moderate, or severe.” The length of time that the AE remains is also important. (8) For instance, there is a major difference between the patient suffering from mild constipation for three days versus a person who suffers two months of severe constipation. The adverse event classification systems include the National Cancer Institute Common Terminology Criteria for Adverse Events, and the Medical Dictionary for Regulatory Activities (MedDRA).
The disaggregating of adverse effects leads to underestimating certain AEs. For example, fatigue may have a several synonyms, such as malaise or tiredness. “Fatigue” for one person is different from “fatigue” for the next person. (8) After completion of the study it is theoretically possible to re-aggregate these symptoms. However, re-aggregation is not accurate. Future trials should carefully define each probable adverse effect.

The studies are underpowered with regard to identifying AEs. Assuming the incidence of one particular AE is one in 1,000 patients, the study needs 3,000 patients in order to uncover one case, with 95% probability. If we want to uncover 3 cases, the study would require 6,500 patients. (9) The numbers in the monoclonal studies were inadequate. The studies also do not extend long enough to adequately assess adverse effects.

Going forward, studies should use a checklist of symptoms. In addition, carefully defining each possible adverse effect would help to avoid “disaggregation” of symptoms. We need to have a more accurate picture of adverse effects coming out of the studies.

References

1. Robbins L., Phenicie B. CGRP Monoclonal Antibodies for Chronic Migraine Prevention: Evaluation of Adverse Effects Using a Checklist. Practicalpain management.com. March-April 2020.
2. Robbins L. CGRP monoclonal antibodies for chronic migraine: year 1 of clinical use. Practical Pain Management. 2019; 19(6):58-62.
3. Robbins L. CGRP antagonists: physiologic effects and serious side effects. Headache. 2018;58(9):1469-1471
4. FDA FAERS Website: https://fis.fda.gov/sense/app/d10be6bb-494e-4cd2-82e4-0135608ddc13/sheet/7a47a261-d58b-4203-a8aa-6d3021737452/state/analysis
5. Robbins L. CGRP monoclonal antibodies for chronic migraine. Practical Pain Management. 2019;19(2):45-52.
6. Robblee JV, Mendez N, Potter J, Slonaker J, Grimsrud KW, Starling AJ. Post-market observational study of patient experience with erenumab. In: Headache. 2019;59(supp 1):48.
7. A New Class of Drug for Migraine Prevention. In: Quarterwatch(a publication of The Institute for Safe Medication Practices)Aug. 2019; Available at: www.ismp.org/quarterwatch
8. Moore T, Assessment and reporting of harm. In: Fundamentals of Clinical Trials, fifth edition, by Friedman L, et al. Springer, 2015. Chapter 12,255-274.
9. Furberg BD, Furberg CD. Evaluating Clinical Research. All that Glitters is Not Gold (2nd edition). New York, NY: Springer, 2007, pp.17-18 10. Ashina M, Goadsby PJ, Reuter U, et al. Sustained efficacy and long-term safety of erenumab in patients with episodic migraine: 4+-year results of a 5-year, open-label treatment period. Presented at: 61st Annual Scientific Meeting of the American Headache Society; July 11-14, 2019; Philadelphia, PA. Oral IOR10.

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