More Research Is Only a Small Part When Addressing the National Opioid Crisis

Response to “Prevention at the Point of Pain” by Mark Wolverton (Penn Medicine, Fall 2017)

The Penn Opioid Task Force is well intentioned, imploring physicians to follow “standardized clinical approaches” in treating pain based on EMR inquiries on past prescription patterns, in order to more responsibly and effectively treat opioid addiction. This is far from enough.

As a board-certified pain physician, formerly working in the Penn Spine Center (I left the health system in 2007), I initially embarked on responding to this article based upon my own personal/professional clinical experience. I planned on describing specific tactics and strategies that I have used over time to most appropriately treat complex and challenging pain patients. I planned on discussing the roles played by numerical pain ratings, patient self-reported functional capacity, physical examination findings, adjuvant analgesics (useful in treating neuropathic pain), and awareness of patient behavioral “red flags,” when prescribing opioids. I had thought that aberrant patient behavior, borne from psychological and physical impairments, was at the root of the opioid crisis. Then I watched the multiple segments from CBS’ 60 Minutes which were based on their own investigative reporting, along with that from the Washington Post, regarding the testimony delivered by a DEA whistle blower. My opinions about the role of the physician as the primary change agent who can address the opioid crisis radically changed.

Mr. Wolverton claimed that “preventing that link (opioid use leading to addiction) from developing begins with the physician (and health care delivery systems).” I originally thought so myself and, armed with my judiciously-utilized prescription pad, have followed the most scrupulous and objective tactics and strategies to avoid fueling the addiction problem among my own patients. I have since learned that a massively larger source of the crisis was the promulgation of intentional, malevolent, and greed-induced policies fostered by the United States government. Yes, I said it.

The investigative reports, listed above, revealed that McKesson, Cardinal Health, and AmerisourceBergen (distributors of more than 85 percent of the opioid supply in this country) had made more than $100 million per week of profits on the sale and distribution of opioid analgesics. Former high-level DEA investigators and enforcement officers were sidelined and muzzled. Lawyers at the DEA, the United States Department of Justice, and U.S. Congressman [Tom] Marino’s legislation all operated in collusion to install a new “Drug Czar” (Mr. Marino himself) to endeavor to eliminate the culpability of the DEA, the opioid distributors, as well as the pharmacies that stocked the opioids. These institutions, which ought to function as flagship examples of a successful democracy, waged quite unscrupulous/criminal campaigns to intentionally fuel the opioid crisis for billions of dollars of profits. Hundreds of thousands of suspicious opioid orders were never reported. The reckless U.S. government institutions, listed above, facilitated a simple raising of the reporting threshold to rig the system to stay under the radar. The opioid distributor, McKesson, was flicked with a fine only around $100M—pocket change for them.

The author suggests that physical therapy, cognitive based therapy, social programs, and multifaceted addiction treatment simply need to be better coordinated. This exercise in futility is analogous to simply mopping up faster in the face of seeming total inability to turn off the fire hose soaking the country in opioid addiction. He continues by suggesting that CDC and other agency efforts “to promulgate physician guidelines for pain management are a step in the right direction.” Unfortunately, this is only a very small step. Now, under the Trump administration, the CDC can’t use the words (in their online and other publications) “evidence-based” and “science based.” So much for scientific integrity.

Fitzgerald’s, Grosser’s, and Woolf’s call for “major and multifaceted scientific initiative to identify better pain treatments by a National Academy of Sciences committee” is unfortunately doomed. A $10 billion research fund studying the neurobiology of pain is unfortunately not “a very cost-effective investment,” as it cannot possibly get “on top of this crisis.” The opioid crisis represents an Orwellian corruption of our democratic and scientific/regulatory institutions that seems insoluble by politically nefarious design.

I certainly agree that we must address the “confluence of political, scientific, and criminal dimensions.” I agree with Dr. Cheatle that “top down reformation (of) legislators … and the pharmaceutical industry” is necessary. Let me know how that goes.

The author recounted Dr. Ashburn as noting that “we’ve (the healthcare system) devolved to using opioids to treat pain and that has caused significant harm to society.” Perhaps this is so, yet clinicians were escorted down the garden path by the opioid industry facilitated by our own government. While “more research and better pain management education are crucial to the solution,” and physicians must “make better choices,” these approaches address but a very small tip of a huge iceberg.

L. Matthew Schwartz, MD, GME‘89

Bioenergetic Medicine: Bring It On!

Response to “Our Electric Symbionts and their Rebel Champion” by David Steen Martin (Penn Medicine, Fall 2017)

Douglas Wallace, PhD, considered a “mitochondriac,” will hopefully bring clinical breakthroughs in mainstream medicine. “Bioenergetics … (and) discoveries linking mitochondria, energy, and disease are converging into an active area in science and coming fast,” asserts the article’s author, Mr. Martin. Bring it on!

Mitochondria regulate the expression of a large proportion of genes in the human genome according to Dr. Wallace. Like mitochondria, their evolutionary precursors, bacteria, found mostly in our guts, influence epigenetic expression by regulating histones, proteins that direct raveling and unraveling of our genome, exposing or hiding certain genes along the long-coded scroll of life for/from protein transcription. Our gut flora radically changes depending on our diets, whether animal- or plant-based.

Inflammation-induced energy depletion leading to mitochondrial DNA mutations has been studied intensively for years. It is fairly widely accepted, within the functional medicine and orthomolecular medicine academic community, that many musculoskeletal and neurological degenerative diseases, autoimmune diseases, fatigue, and even cancer represent multi-organ involvement as a variably expressed constellation of symptoms and disease manifestations apropos of this process.

Culprits have been identified. Sugar, starch (that turns to sugar), alcohol, animal fats (high in omega-6 fatty acids), medications (e.g. statins, metformin, antidepressants, and others), and legions of neurotoxins to which we are exposed (even in-utero) in our air, water, and food supply—all are pro-inflammatory and have been shown to be toxic to mitochondria.

There was a brief mention in Mr. Martin’s article of a practical clinical approach to mitochondriopathy. “Attentive clinical care, exercise, vitamins, and nutritional supplements, while avoiding medications known to be toxic to mitochondria” are necessary interventions, yet no further detail was offered.

Many effective therapeutic strategies have been identified. A diet high in plant-based proteins, fats, and complex carbohydrates is essential, for antioxidants and natural anti-inflammatories. Sleep restoration, stress management, minimization of toxin exposure (reverse osmosis water filtration, organic foods), and high-intensity interval agility, strengthening, and endurance exercises are also very valuable.  Supplements like Co-Enzyme Q10, DHA fish oil (docosahexaenoic acid), probiotics and high-dose Vitamin D3, L-Carnitine, and D-Ribose have all been considered energetically restorative.

Mr. Martin implicates the “naysayers … (who) have considered his (Dr. Wallace’s) focus … misguided and his findings irrelevant.” I wonder if these naysayers have any allegiance to maintaining the status quo conventional disease-care model. I look forward to research outcomes which might elucidate etiologic factors and provide clinical recommendations for targeted practical and lower-cost behavioral changes that could slow/reverse mitochondriopathies, rather than predictably simply seek a billion-dollar pharmaceutical “solution.” This burgeoning field deserves more than just a magic pill.

L. Matthew Schwartz, MD, GME‘89

Learning from “Special” Diseases in History

Response to “Cancer and the Costs of Special Treatment” by Janet Weiner, PhD (Penn Medicine, Fall 2017)

Dr. Weiner’s article was interesting and informative. Some historical perspective may further inform the discussion. At various times in history certain illnesses have provoked more fear than others and so earn the title “special.” Some examples are leprosy, bubonic plaque and the 1918 flu epidemic.

Tuberculosis perhaps most closely resembles the current attitude toward cancer. Although an ancient disease, it was only in the Middle Ages/Renaissance that it displaced leprosy as a leading cause of death. By the 19th century the disease took on great fear and a romantic connotation, and the disease influenced other aspects of society (art and literature). More importantly, from a medical perspective, the “specialness” of the disease spurred research and laid the groundwork for much of modern microbiology (e.g., Koch’s bacillus), leading to vaccination and antibiotics. The costs of many illnesses were lowered and life expectancy was dramatically prolonged.

The AIDS epidemic at the end of the 20th century also acquired a certain “specialness” which provided political activism to stimulate the allocation of research resources. This led not only to the containment of the disease but also great insights into the workings of the immune system. The “fallout” of this knowledge is now being used in the development of precision immunotherapy medicines for cancer care.

Looking back on the history of medicine one cannot but marvel at the ability of humankind to understand and find treatments for various diseases. The “fallout” from the allocation of resources to research “special” diseases is not always predictable and may have influence far beyond the treatment for the “feared” disease (as Dr. Weiner points out in her article). Finding the proper balance between costs and benefits is not easy. Adding an unknown factor (the accrual of basic science and medical knowledge) further confounds the problem. The Gant consortium is to be commended for taking on this difficult, multifaceted conundrum.

Edward W. Gerner, MD, GME’69

Albert Winegrad’s Legacy of Mentorship

Albert Winegrad

Albert I. Winegrad, MD

We were saddened to learn of the death of Albert I. Winegrad, MD, formerly Willard and Rhoda Ware Professor of Diabetes & Metabolic Diseases, and director of the George S. Cox Medical Research Institute. His obituary published in the last volume of Penn Medicine failed to note one of Dr. Winegrad’s important but unsung contributions to the School of Medicine, his mentoring of future physician-scientists at all levels, medical students, residents, fellows and junior faculty.

Each of us was touched by Dr. Winegrad while we were medical students at Penn, and each of us is profoundly grateful for the influence he had on our career choices. Despite his international reputation in diabetes research, particularly the pathophysiology of diabetic neuropathy, Winegrad was not visible to medical students. He was not outgoing to say the least; you had to be directed to him by one the cognoscenti.

Those who were fortunate to find their way to his laboratory were richly rewarded. His office door opened to his laboratory so he could observe all that was going on, which he did. Although the door was always open, if you wanted to speak with him you had to navigate a maze made up of stacks of issues of the Journal of Clinical Investigation and the Journal of Biological Chemistry to get to a chair. The maze, no doubt, was the physical embodiment of his personality—not easily approached, guarded and shy. However, once the maze was traversed and the seat taken, he would open up and dispense invaluable wisdom.

Dr. Winegrad had an incredible fund of knowledge of physiological chemistry and metabolism. That was not surprising, since he continued the tradition of earlier giants in diabetes research at Penn, the physician-scientists Francis D. W. Lukens and William C. Stadie. A meeting with Dr. Winegrad was filled with probing questions about experimental design or results; insightful critiques of recent publications; and, usually, his commentary, often stinging, on the state of medical education and research. But above all, these séances were about teaching critical thinking, and instilling a passion for translational research, well before that term became common parlance. You walked away from the meeting a little humbled, but exhilarated about the science.

Michael S. Brown, MD’66

Edward W. Holmes, MD’67

Jerome F. Strauss III, MD’73, PhD’75, GME’76

Individual Remembrances of Winegrad

Al Winegrad made a huge impression on me, and he had a huge influence on my career. I had my first research experience in his lab, and he taught me how to be critical. I have always been grateful. Al helped me to secure my internship in medicine at the Massachusetts General Hospital, and it was there that I met Joe Goldstein and initiated a research partnership that has endured for nearly half a century. As my reputation in science grew, Al was always friendly to me, and I think he was proud of my accomplishments, but his unusual personality somehow made him shy about initiating contact. His personality also made him a lonely figure at Penn. He was critical of the direction that Penn took in the 1970s and he made no secret about his opinion. I was gratified when Al received the Banting Medal, the highest honor of the American Diabetes Association. I think he was profoundly disappointed when clinical trials of aldose reductase inhibitors failed to confirm his theory that sorbitol was the offending agent in diabetic complications. He was a dedicated physician-scientist, a profound teacher of science, and a model medical school professor. – Michael S. Brown

Like many in my medical school class of ’67 I had little knowledge of academic medicine and no experience in biomedical research when I entered med school. When I started my medicine rotation on Ward B my attending was a physician-scientist and as the rotation progressed I was introduced to a new way of thinking about patients and the underlying causes of their clinical disorders. I was invited to join this individual’s laboratory during the summer break and for an elective rotation during my senior year. My experience in the laboratory introduced me to the excitement and challenge of trying to understand a clinical problem at a fundamental level. I learned how to ask questions and how to design experiments to address these questions. At the same time my interest in clinical medicine continued to grow. This experience cemented the desire on my part to become a physician-scientist and ended up shaping what has turned out to be an exciting and rewarding career in biomedical research and academic medicine. I have had a number of wonderful mentors over the years but absent this encounter with someone who was a superb clinician and a dedicated scientist at this early stage in my medical career I may never have had the opportunity to pursue a career as a physician scientist. Thank you Al (it was only when I returned to Penn as chair of Medicine that I felt comfortable addressing Dr. Winegrad by his given name) for being a role model and mentor. I join with the others who had the opportunity to work with you in celebrating your career at the University of Pennsylvania. – Edward W. Holmes

My path to Dr. Winegrad’s door started with a recommendation from one of the cognoscenti. I had an idea about how glucose metabolism might regulate steroid hormone metabolism, but was clueless as to the best way to test the hypothesis. The late David B.P. Goodman (MD’68, PhD’72), who had published with Dr. Winegrad as a student, and subsequently became a professor of Pathology and Laboratory Medicine and director of the hospital’s William Pepper Laboratories, heard my story and told me that I had to speak with “the man.” I did, and was welcomed into the Winegrad laboratory as a “guest.” I learned how to measure glucose flux in tissue slices, but more importantly, Dr. Winegrad helped me refine my working model and experimental design. I had never before been pushed to defend my thinking in such depth, and boy was it eye-opening. In the process, I learned more about metabolism than I did from any coursework. Although I am grateful for the specific scientific advice, I am most appreciative of Dr. Winegrad’s encouragement, which kept me anchored to academic medicine; his teachings on the approach to medical research, which left a lasting imprint; and his mentorship. I relied on the latter extensively during my career and in my role as director of the Medical Scientist Training Program at Penn. – Jerome F. Strass III 

Editor’s note: The following letter was received after the Winter 2018 issue of the magazine was published:

I worked with Dr. Winegrad in the Cox institute from 1967 through 1969 when I graduated from Penn. He happened to have been one of the most influential persons in my entire life’s journey, as I came to him with a personal dilemma I was living through in early 1967.

I met a Penn student in the medical school library in 1967. She was a Penn nursing student, and I fell in love. We had dated for about two months when she revealed that she was a type 1 diabetic who had been a diabetic since age 11.

Needless to say, that was my second year in medical school—the year we study pathology. This came as a shock to me, and I was lost: I had met this beautiful woman—intelligent, sensitive, and thoughtful- but I was thoroughly aware of the range of pathology with this diagnosis. I had no idea what I should do!

I decided to go to the only person who I believed had the best knowledge of this disease who could counsel me with all the implications of potential problems. So I went to “Dr. Winegrad” expecting some guidance with my dilemma.

I don’t remember how long we talked—it was over 50 years ago—but I remember the essence of the content: “Al” went into the range of the pathology with type one patients, and the range of “marriages” and concluded that the best thing I could do was to “follow my heart.” This was one of the most “caring” discussions I have ever had with anyone, as I did follow my heart as he suggested, and Anne and I had our 50th wedding anniversary this past December. She is still in good health!

As I have thought about this for years, it is exemplary of the “heart” of the man: Dr. Albert I. Winegrad. He took a young, in love, medical student, and guided him down a road to 50 years of blessings, two children, and three grandchildren.

I have held him in my heart since that encounter. I definitely chose the best person to share my worries with. He will be missed. — James P. Weaver, MD ‘69

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