Opioids: How We Got Here, Where We Go From Here

First in a Series about Work Being Done at VP&S to Understand, Treat, and Prevent Opioid Addiction
By Sharon Tregaskis | Illustrations by Davide Bonazzi

William Head “Will” Williams was the kind of person who might have entered VP&S as a medical student, says his father, Bill Williams. He was bright, vivacious, a voracious learner. Instead, Will entered VP&S in 2012 as an anatomical donation, dead at age 24 from an accidental heroin overdose.

Will had a mix of anxiety and attention deficit hyperactivity disorder that made school a rough fit. Studying from home in his senior year, he thrived—mixing tutoring in AP physics and AP calculus with two internships as a day trader. When he turned 18 that year, he plunged into active trading full time, earning enough as a day trader by age 20 to fund a trip around the world. 

He also had a passion for martial arts, says his father, and at some point, his martial arts instructor, a man he considered a mentor, introduced him to heroin. He began by snorting. The instructor suggested that Will’s occasional use—“chipping”—would not lead to addiction. 

“But it was a problem for William,” says his dad. “It was the beginning of the end.” Will was 22 when a friend of his called to alert Mr. Williams and his wife, Margot Head, that their son was using heroin. The friend, worried about Will’s safety, described Will as out of control. Over the next two years, Will tried everything: outpatient and inpatient treatment, 12-step programs, and inpatient and outpatient detox, punctuated by multiple overdose-related emergency room visits. “The Greek word agonycomes from a wrestling match, a contest,” says Mr. Williams, a retired high school theater teacher. “The agony of an addict—at least for William—was the contest between wanting to recover from his addiction and the siren call of the drugs.”

Following a final overdose, Will’s heart stopped beating. After being revived by EMS, he spent more than six weeks in the hospital. He first underwent a protocol called therapeutic hypothermia in an attempt to assist and preserve neurologic function. He was sedated to help avoid seizures and further brain damage, and his brain was scanned regularly. It became clear that his brain had been damaged beyond repair by the lack of oxygen in the crucial minutes he was in cardiac arrest. “While his heart function was restored, the damage to his brain was too great,” Mr. Williams says.

Intent that Will’s death not be in vain, his parents and his sister, Elizabeth Hope, decided to donate his body to VP&S after removing him from life support. “In another time, in a better era,” says his father, “William might have entered the College of Physicians and Surgeons not as a cadaver but as the gifted and talented young man he was.”

Images of Will’s tissues now illustrate the digital manual provided to VP&S students as their guide to anatomy training. His parents have become tireless crusaders in the campaign to confront opioid addiction and prevent overdoses, which killed more than 42,000 Americans in 2016—a record number—and was the No. 1 killer of Americans under age 50. 

Will Williams on a visit to the New York Stock Exchange

An Epidemic is Born

Any brief explanation of how the opioid epidemic began would be an irresponsible simplification. The epidemic likely has many roots, some dating back to the 19th century. Street drugs—such as those used by Will Williams—have been around for decades, and aggressive tactics by pushers have contributed to their popularity. Their cheap price, the role of organized crime in importing and distributing them, and their increasing potency—sometimes from dangerous combinations of ingredients—have been factors in the upward trend of use of drugs in all socioeconomic communities.

The blame for the current epidemic, then, can be placed on any number of factors that might explain the hold drugs now have on American life, but the more recent escalation of the opioid epidemic points toward prescription opioids. The vast majority of the 11.8 million Americans who reported using opioids in 2016 consumed not heroin but prescription pain relievers, according to the federal Substance Abuse and Mental Health Services Administration. Only 13 percent of individuals who misused pain relievers—by taking them at a higher dose or at greater frequency than their physician had directed—took them to get high. More than 60 percent were attempting to relieve pain. Some used prescriptions that were not theirs—by using medication prescribed to others, stealing opioids from medicine cabinets, or using drugs supplied at parties. Though the CDC reported that only 40 percent of all opioid overdose deaths in 2016 involved a prescription opioid, the numbers do not indicate how many of the other 60 percent died from using illegal drugs they sought out after becoming addicted to prescription opioids.

The rise in the availability of prescription opioids began in the 1980s, when pharma started marketing what seemed at the time to be breakthroughs in manufacturing that allowed for higher-dose, time-release formulations. Before then, opioids were considered so risky they were offered only to end-stage cancer patients and to people who had recently had major surgery. Suddenly opioids seemed like a viable solution to all manner of chronic aches and pains. Vicodin became the No. 1 prescription drug in America.

By the late 1990s, the stage was set. In a New York Times Magazine essay, Columbia oncologist Siddhartha Mukherjee, MD, DPhil, reflected on his own first encounter, in 2001, with a patient addicted to opioids. “Pain, we had been told as medical residents, was being poorly treated (true)—and pharmaceutical companies were trying to convince us daily that a combination of long- and short-acting opioids could cure virtually any form of it with minimal side effects (not true).” 

In the early 1980s, prescription opioid formulations were limited to morphine and codeine. Vicodin was approved by the FDA in 1984; extended-release OxyContin and Percocet came along by the end of the 1990s. 

Americans use 80 percent of the world’s opioids, which some blame on society’s expectation that all problems can be fixed and all pain can be managed and alleviated.

It is hard to know the kind of pain people are treating when they misuse opioids. While some have medically documented physical maladies—chronic back or knee pain from a jobsite injury or home improvement mishap, for example—a growing body of scholarship suggests that mental health problems, including anxiety and depressive disorders, post-traumatic stress disorder, and the more diffuse mental anxieties stemming from widening income inequality and other stressors of modern life, also could play a part in the skyrocketing popularity of opioids. “The problem is complex, with multiple factors likely to be interacting with each other,” says epidemiologist Deborah Hasin, PhD. “If opioids weren’t so widely available, people at risk for addiction due to, say, economic distress, might be using some other substance instead. However, the wide supply of opioids, particularly those initially obtained through prescriptions, has certainly been a major contributor to the problem.” 

Americans use 80 percent of the world’s opioids, which some blame on society’s expectation that all problems can be fixed and all pain can be managed and alleviated.

Meanwhile, with individuals continuing to use opioids, and in the absence of a silver bullet to halt the crisis in its tracks, Dr. Hasin and other epidemiologists have their work cut out for them, answering an array of questions about the characteristics of users and prescribers to inform targeted prevention and treatment interventions as well as analyses of the efficacy of interventions such as state prescription drug monitoring programs and new pain clinic regulations. Research is also needed on the most effective public and medical education programs to promote more informed opioid prescribing patterns and possible alternative pain treatments. “Many aspects of the needed data are there and just need to be harnessed to answer these questions,” says Dr. Hasin, who runs Columbia’s substance use epidemiology training program. “However, these efforts require time, effort, and research funding. At the same time, other potential risk factors and solutions require new data collection to provide the information to better understand the opioid problem and its solutions, which are likely to be at multiple societal and individual levels.” 


How Opioids Work

Like other addictive substances, opioids affect dopamine, a foundation of the biochemical communication system within the brain responsible for memory, learning, and reward. “In many diseases, there’s clearly something wrong with the body,” says neuroscientist David Sulzer, PhD. In heart disease, the cardiovascular system has a glitch. In cancer, cellular replication and division have gone amiss. “Addiction is different,” says the scientist, who investigates how dopamine signaling goes wrong in such disorders as Parkinson’s and schizophrenia.

In addiction, Dr. Sulzer says, the brain is actually doing what it is programmed to do: The biochemical reward system in the brain—the dopamine release that spurs action in anticipation of a reward—is triggered. “Opioids hijack those mechanisms to reinforce their own acquisition,” says Dr. Sulzer, whose research portfolio also includes studies of the mechanisms by which addictive drugs alter dopamine signaling. If your leg breaks, doctors can set and cast it. If your cholesterol is too high, a statin might bring your blood chemistry back to its target range. Interrupt the basic function of dopamine signaling in a bid to short-circuit addiction, however, and such fundamental human activities as learning, memory formation, and the joy of completing a task go by the wayside. 

Opioids disrupt the dopamine system through two synergistic mechanisms: They make the neurons that release dopamine more responsive and increase the amount of dopamine released each time the neurons fire. While each opioid varies, in terms of its dose-response effect and the tolerance it induces, opioids as a group represent a double whammy in terms of positive reinforcement.


Opioids Have Their Place

Despite the intense scrutiny surrounding the damage opioids inflict, clinicians agree that opioids have a place in treatment protocols. Finding the patients who need them and will tolerate them without becoming addicted is a key challenge, but clinicians in pain management also grapple with the absence of measures to quantify and independently verify pain, to assess the extent to which it impedes function or compromises quality of life. 

Acknowledging that one of the causes of the current opioid epidemic is prescription medicines, the medical community, academic medicine, and government are looking for solutions that preserve the use of opioids when medically indicated. Several neurosurgery groups have come together to work with the FDA on recommendations that would create medical documentation to justify prescriptions of opioids. “Like other surgeons and clinicians, we are concerned about the impact of the opioid crisis, but we want to preserve patient access to opioids that are medically necessary,” says Columbia neurosurgeon Christopher Winfree’96, former president of the American Association of Neurological Surgeons/Congress of Neurological Surgeons Joint Section on Pain. “We are confident that we will be able to work with the FDA on a solution that reduces the overall availability of opioids to limit them to clinical situations that warrant their use.”

Over the past year, a working group led by James Peacock, MD, associate chief medical officer at NewYork-Presbyterian, tackled similar questions on behalf of physicians associated with the hospital, including Columbia and Weill Cornell faculty practices, hospitalists, the NYP emergency department, and outpatient practices overseen by NYP. The group developed a dashboard to help clinicians and researchers analyze opioid prescribing patterns and determine patients at risk for addiction. “We’re not saying we should bring prescriptions to zero,” says Dr. Peacock. “There is a place for opioids in medicine, but we need to make sure medications are appropriate.”

In March, as part of Columbia’s celebration of National Patient Safety Awareness Week, ColumbiaDoctors and Columbia’s nursing school collaborated to provide training meant to combat the opioid epidemic. “Our ColumbiaDoctors personnel are standing on the front lines of this epidemic,” says chief medical officer Shunichi “Nick” Homma, MD, “and through this initiative we will better equip them with needed training to save lives that might otherwise be lost to opioid overdoses.”

In December 2017, the Irving Institute for Clinical and Translational Research hosted a brainstorming session about the opioid crisis, inviting experts from throughout Columbia, NewYork-Presbyterian Hospital, the New York State Psychiatric Institute, and Northern Manhattan community organizations. More than 60 individuals participated in discussions and presentations on ongoing research and treatment program innovations, intent on developing strategies to end the crisis. A larger symposium is planned for June 2018.

Who’s Who

Nigel Bunnett, PhD, the Gerald and Janet Carrus Professor of Surgical Science (in Surgery and Pharmacology) and vice chair of research in surgery

Deborah Hasin, PhD, professor of epidemiology (in psychiatry)

René Hen, PhD, professor of neuroscience and pharma-cology (in psychiatry) and chief of the Division of Systems Neuroscience at the New York State Psychiatric Institute

Shunichi “Nick” Homma, MD, the Margaret Milliken Hatch Professor of Medicine (in Biomedical Engineering), deputy chief of the cardiology division, and chief medical officer of ColumbiaDoctors

Jonathan Javitch, MD, PhD, the Lieber Professor of Experimental Therapeutics (in Psychiatry), professor of pharmacology (in the Center for Molecular Recognition and in physiology & cellular biophysics), and chief of the Division of Molecular Therapeutics at the New York State Psychiatric Institute

Siddhartha Mukherjee, MD, DPhil, associate professor of medicine

James Peacock, MD, assistant professor of medicine

David Sulzer, PhD, professor of neurobiology (in psychiatry, neurology, and pharmacology) at CUMC

Christopher Winfree, MD, assistant professor of neurological surgery

Building a Better Pain Reliever

Imagine that physicians did not need to find a way to identify which patients could tolerate opioids or develop safeguards to restrict their abuse. Research by Nigel Bunnett, PhD, focuses on finding better ways to alleviate pain.

Dr. Bunnett witnessed firsthand the shortcomings of opioids—even for people with terminal cancer—when his mother was dying. Doctors prescribed morphine to help her cope with the pain, but eventually the resulting constipation became so painful she opted to forgo the opioids. “Morphine is thousands of years old,” says Dr. Bunnett. “We’ve got to do better for patients.” 

And so for more than 30 years, the English-born scientist has investigated the biochemistry of G protein-coupled receptors (GPCRs), a family of more than 850 proteins that carry messages—including pain signals—from outside the cell membrane to the cell interior. In recent years, he’s homed in on the role of endosomes, the acidic, membrane-bound vesicles central to the movement of molecules into and through the cell. “Until very recently, it was thought that endosomes were just a conduit for processing of receptors,” says Dr. Bunnett. “It was also thought that receptors only signaled from the surface of the cells and drugs were developed to target these cell surface receptors.”

Over the course of the past decade, Dr. Bunnett and his collaborators have revealed that GPCRs continue to signal from within intercellular spaces, that those signals can be prolonged, and that they are central to the transmission of pain signals. Taken together, those findings begin to suggest why some pain medications have limited effectiveness: They are designed to target cell surface GPCRs, may not cross the lipid-rich cell membrane, and may be unable to interact with GPCRs in the comparatively acidic environment inside endosomes. “The development of drugs designed to target these receptors in the right subcellular location is important,” says Dr. Bunnett. “We already have medications that target receptors in particular tissues or cells, but we want to target them to particular organelles. It’s a new approach for drug delivery.”

In 2018, Dr. Bunnett and his collaborators incorporated Endosomal Therapeutics to spur drug delivery innovations and the identification of compounds that leverage those insights. Current work includes chemical engineering to convey drugs directly to the endosome by bonding them to lipids or encapsulating them within nanoparticles and structural analyses of individual GPCRs to identify compounds that will remain bound to the receptor in an acidic environment. “I see this as a great way of actually taking a compound all the way to a drug that could help people.”

The antidepressant tianeptine already helps people—in Europe, Asia, and South America. It lacks the sexual side effects of antidepressant compounds approved for use in the United States and appears to be effective in patients who do not respond to other drugs. Despite its use in tens of millions of patients over the past several decades, scientists did not know its molecular target in the brain. Several years ago, Columbia chemists Andrew Kruegel, PhD, and Dalibor Sames, PhD, teamed with Jonathan Javitch, MD, PhD, chief of molecular therapeutics in psychiatry, to show that tianeptine is a selective and efficacious mu-opioid receptor agonist, leading them to hypothesize that this receptor is the target through which tianeptine functions. With early support from the VP&S Interdisciplinary Research Initiatives Seed Program, the group teamed with neuroscientist René Hen, PhD, an expert on animal models of depression, to explore the behavioral effects of tianeptine. In studies using mice, published in the journal Neuropsychopharmacology, the team confirmed that tianeptine’s antidepressant and antianxiety effects are mediated by the brain’s mu-opioid receptors. This was a remarkable finding, given that other agonists of this GPCR, like morphine, heroin, and fentanyl, have previously been known only in the context of their use as powerful pain relievers, where addiction, tolerance, and physical side effects such as respiratory depression present major challenges.

Next issue: treatment and education strategies

In contrast, the rate of abuse with prescribed tianeptine is extremely low, and in mice, the team has shown that the compound does not induce the tolerance or withdrawal symptoms associated with morphine and other opioids. “Not all mu-opioid agonists are the same,” says Dr. Javitch. He and his colleagues have been driven by this discovery to explore in detail such “atypical opioids,” which have distinct effects compared with classical opioid drugs. Critical next steps are to understand how different opioid compounds diverge at the level of their molecular signaling and to identify the precise brain circuits at which they exert their therapeutic effects or side effects. Ultimately, this will allow scientists to design new opioid drugs that provide therapeutic effects with fewer negative side effects. In 2017, Drs. Hen, Javitch, and their chemist colleagues cofounded a new startup, Kures Inc., to try to bring a novel tianeptine analog, synthesized at Columbia, to human use, with the hope that it will be effective in patients where currently available antidepressants fail. The team is also expanding its investigation of atypical opioids—including the active compounds of kratom (Mitragyna speciosa), an evergreen plant native to Southeast Asia—to characterize their structure and biological effect in search of signaling profiles that could be modulated to selectively reduce pain or depression without impairing respiration or gut function or triggering addiction. 


Breaking the Cycle

Throughout the medical center campus and beyond, efforts are underway to come to grips with the opioids problem and find solutions, whether they lie in creating better pain relievers, improving ways to measure pain, or unraveling the mystery of why some patients can tolerate opioids and others become addicted.


Read an essay by Bill Williams here.