By Mark Wolverton | Photos by Tommy Leonardi

Penn Medicine clinicians and scientists are taking on the national opioid crisis where it began: the causes and treatment of pain.

The United States is in the grip of an opioid crisis. Drug overdoses, mostly from opioids, are now the leading cause of death for adults under 50, with an average death toll of 142 Americans each day drawing a comparison, by a presidential commission, to a “September 11 every three weeks.”

In Philadelphia, Penn Medicine clinicians are on the front lines. The city has the third highest number of overdose fatalities in the U.S., according to the Centers for Disease Control and Prevention (CDC). “I’ve had shifts where I’ve treated multiple heroin overdoses,” says M. Kit Delgado, MD, MS, an assistant professor of Emergency Medicine. His experience is borne out by the recent mayor’s task force report noting an estimated 70,000 heroin users in the city. Yet often overlooked in media coverage about heroin addiction and drug-infested urban war zones is that the crisis largely originated not with the criminal underworld but in the office of the family doctor or dentist.

When he talks to patients about their heroin use after an overdose reversal, Delgado says, “the vast majority of them started after being exposed to prescription pain medication.” People who picked up a relative’s leftover pills to self-medicate, or who trusted their doctor to provide relief from chronic pain conditions such as back pain or arthritis, or from the pain of a routine surgical procedure, found themselves dependent, addicted, and sometimes dying—not because they started out looking to get high, but because something went badly awry when their doctors were trying give proper care for pain.

National Institutes of Health Director Francis Collins, MD, PhD, and National Institute on Drug Abuse Director Nora Volkow, MD, recently wrote in the New England Journal of Medicine that “science is one of the strongest allies in resolving public health crises. Ending the opioid epidemic will not be any different.” Penn Medicine’s opioid task force has a number of efforts underway to help patients experiencing addiction, including smoother transitions into medical therapy for opioid use disorder from the emergency department or from inpatient care for other conditions. At the same time, physicians, researchers, and primary care providers at Penn are using science to battle the opioid crisis from the other end, where it began: the causes and treatment of pain.

Tell Me Why It Hurts

It’s a daunting challenge because of the very nature of pain. A fractured collarbone is just that, but pain isn’t that straightforward. Unlike objective clinical measures like blood pressure, pain scales measure what patients report. And what one person experiences as excruciating, another might shrug off as mere temporary discomfort, like a quarterback spraining his ankle yet continuing to play in a championship game.

Another problem is that pain is maddeningly complex even at its most fundamental physiological and molecular level. Pain signals are transmitted through a large number of different ion channels and nerve endings via multiple mechanisms. Those different mechanisms also contribute to different sensations and perceptions. The inflammatory pain of arthritis isn’t the same as a migraine headache, for example, because different mechanisms create each.  

Doctors confront pain with a relatively limited set of treatment options. For major surgery, trauma, and cancer, the most powerful choice is opioids. For what’s generally termed as “non-malignant chronic pain,” choices are fuzzier. The usual non-addictive alternative to opioids is non-steroidal anti-inflammatory drugs (NSAIDs), familiar to everyone in over-the-counter forms such as Motrin, Advil, and Aleve. But as their name implies, NSAIDs are thought to be effective for inflammatory-based pain and virtually nothing else. And like all medications, they have side effects, including gastrointestinal irritation and bleeding, increased blood pressure, kidney problems, and even serious cardiovascular complications such as heart attack. For these reasons and others, NSAIDs simply aren’t a choice for many patients.

Tilo Grosser, MD, a research associate professor of Pharmacology, whose research focuses mostly on NSAIDs and the mechanisms that drive their cardiovascular side effects, points out that just as NSAIDs should work best for inflammatory pain and not for other types, the same idea of specificity to certain types of pain applies to other pain drugs, including opioids. But the dearth of good research makes it difficult for doctors to know what drug works best for what type of pain. “That’s why understanding the mechanisms that drive the pain process is so critically important,” he says. “If we have a better handle on understanding what drives the pain process in a given patient, then we can target therapy for that individual patient much better.”

But for too long, at least pharmacologically, the choice has been “basically opioids or NSAIDs,” says Garret FitzGerald, MD, the Robert L. McNeil, Jr. Professor in Translational Medicine and Therapeutics. “There have been no new analgesics brought to market in 7 years.” For clinicians, too often that leaves the easy choice of prescribing opioids.

Which, in part, led to the situation today: “The data are very clear that physicians as a group overprescribe opioids,” notes Michael Ashburn, MD, a professor of Anesthesiology and Critical Care and director of the Penn Pain Medicine Center. “The U.S. makes up about 4.4 percent of the world’s population, yet we use about 50 percent of the world’s supply of opioids.”

Jeanmarie Perrone, MD is a founding member of Penn Medicine's task force to address the opioid crisis.

How It All Started

That prescribing opioids is easy doesn’t fully explain the present crisis, but it contributes.

Beyond the ease of prescribing, a fundamental shift in attitudes over recent decades precipitated the explosive growth in U.S. opioid prescribing. In the 1980s, a handful of editorials in the medical literature sparked a movement, fueled at least in part by the pharmaceutical industry, to extrapolate end-of-life pain care to nonmalignant pain patients. The naïve notion was that “no one should suffer,” says Martin Cheatle, PhD, an associate professor of Psychology in Psychiatry at the Penn Center for Studies of Addiction. Jeanmarie Perrone, MD, a professor of Emergency Medicine and director of Medical Toxicology, who is a founding member of Penn Medicine’s opioid task force, traces the liberalization of opioid prescribing in the 1990s to a huge campaign to physicians misleading them to thinking that addiction was rare. For busy primary-care providers, Cheatle notes, the rising demand to treat more patients in less time made it all too easy to prescribe opioids routinely for even relatively minor pain complaints. It had become the automatic response, a routine practice, a one-size-fits-all solution.

The prescribing of opioids had, in fact, become so reflexive that it was enshrined in hospital computer systems. Delgado recalls, from a decade ago during his residency when electronic medical records at his hospital were new, “when you typed in the medication, for example Vicodin, the prepopulated number of tablets was 30 tablets. And so that’s what was getting written. There was no thought as to what the patient actually needed.”

Although the value of opioids for treating pain is well established and has never been at issue, their perceived value, both from the viewpoint of patients and too many doctors, has pushed aside other options, for physicians and patients alike.

Physicians report that managing patients’ pain without opioids requires a lot of education. “A colleague of mine says that it takes 30 seconds to say yes and 30 minutes to say no,” Cheatle says. Many patients believe that they should be completely pain-free, which is not a realistic prospect. But that belief leads patients to expect, for example, a prescription for Percocet instead of Tylenol, because they are convinced the strongest medication is best and anything available over the counter won’t suffice.

“There’s a spectrum here,” says Garret FitzGerald. “If you’re dying of cancer, you have a reasonable expectation that your pain should be managed, because frankly that is the dominant requirement, as opposed to, are you going to be addicted in 3 months’ time? Because you probably won’t be alive in 3 months’ time. But is it a reasonable expectation that somebody who has a back strain or pulls their muscle playing football has a complete absence of pain? What’s the tradeoff between relief of pain and risk?”

In managing that tradeoff, the question of whether opioids are even the best available choice is key.

Opioid drugs are so powerful because they work by switching off pain signaling in the central nervous system, Tilo Grosser explains. But for many types of pain, as for example in inflammatory processes, it may not be necessary to completely “switch off” the pain signal. “You may just be able to treat the source of the pain rather than shutting the pain transmission off through opioids.

A phenomenon by which opioids can transform acute pain into chronic pain is another factor contributing to the crisis. When a person recovering from injury or surgery is prescribed opioids, they’re at risk for slipping into a downward spiral leading to physical dependence and sometimes addiction. Perrone, from Penn Medicine’s opioid task force, cites the statistic that, once you’ve taken an opioid for even one day, there is a 6 percent risk of still being on an opioid medication by prescription a year later even if the original source of pain, such as an injury or surgery, is far in the rear-view mirror. “There’s no question that they have an attraction and a ‘stickiness’ rate that’s certainly much higher than a normal pain reliever,” she says.

M. Kit Delgado, MD, MS, recalls that in the early days of electronic medical records, the default opioid prescription might be for as many as 30 pills. “There was no thought as to what the patient actually needed.”

Preventing that link from developing begins with the physician. Many national and local efforts to address the opioid crisis, including Penn’s, focus on education of both patients and physicians to reduce initial opioid prescribing and thereby reduce the rate at which an instance of acute pain may transform into chronic pain.

There are many other things besides opioids and even non-opioid medications that can be effective for the treatment of pain, Michael Ashburn points out. Physical therapy, exercise, and psychological approaches such as cognitive-behavioral therapy (CBT) or even meditation, can be quite effective for many patients. Unfortunately, Ashburn says, “over the last 20 years, our ability to provide that care has actually worsened.”

Ashburn is referring to the advent of managed care programs and insurance policies that disrupted a more balanced approach to pain treatment. He says the best pain care integrates several different pain treatment modalities. Physician care, mental health care, physical therapy, and other interventions are integrated with proper medication use—and the physician, psychologist, and physical therapist create that plan together after all have seen the patient. The plan can include everything from changing the patient’s lifestyle by teaching them about their condition and how to self-manage their pain to the appropriate use of medications, preferably non-opioid—but only, Ashburn says, “rarely, in carefully selected patients, properly using opioids as part of the solution but not as the solution.”

But because managed care and insurance company policies have fragmented such programs, Ashburn notes, “we’ve devolved to using opioids to treat pain. And that has caused significant harm to society.”

Making Better Choices

Michael Ashburn, MD, laments the loss of multidisciplinary, integrated pain care models.

As with Ashburn’s emphasis on integrated pain care, most of the professionals who deal with the ravages of acute and chronic pain emphasize that alternative or complementary approaches that don’t involve drugs at all, in addition to more research and better pain management education, are crucial to the solution.

Informed guidelines and protocols can help doctors be better stewards of opioids while helping patients get the pain care they need. With that goal in mind, the Penn opioid task force is developing a standardized approach for Penn Medicine clinicians to follow in treating pain, based on intensive study of electronic medical records to determine past prescribing patterns. Perrone points out that such investigations can tease out troublesome patterns of which overworked providers might not even be aware.

“It’s all in the electronic medical record; we have tons of data,” she says. And that data makes it possible to demonstrate extremes of prescribing to help doctors change their prescribing practices: If hard data indicate that a particular doctor might be prescribing opioids more frequently than his or her colleagues, it might inspire a bit more awareness and introspection. “I think one of the few ways that moves a physician’s practice is provider feedback,” she says.

The guidelines are being written for different factors based on direct experience, adjusting prescription amounts through patient surveys to learn exactly how many pills they actually used after a particular procedure. For example, Perrone notes that there was no standard answer to the question, “How many Percocet (if any) do you need after a procedure?” Delgado and Ashburn have partnered with Brian Sennett, MD’88, and Samir Mehta, MD, from the department of Orthopaedics for an initiative to answer that question among patients undergoing knee arthroscopies and other common orthopedic procedures. They aim to develop new prescribing protocols that better provide what patients actually need and reduce the excess number of opioid pills prescribed.

Reducing the supply of excess prescribed opioids is important not only for protecting the patient but those around them. Many patients with opioid use disorder began not as patients under treatment for pain, but simply because they happened upon some extra pills abandoned in the family medicine cabinet, or because a well-meaning friend offered them leftover pills to blunt the pain of a minor injury.

Efforts in recent years by the CDC and other agencies to promulgate physician guidelines for pain management are a step in the right direction. But without the resources to support alternatives, guidelines are only of limited value. Describing CDC guidelines to attempt CBT and physical therapy before considering opioid therapy as “common sense and good practice,” Cheatle notes, there is a serious roadblock. “Access to these therapies is limited and reimbursement is poor or nonexistent,” he says. “We just don’t reimburse for cognitive medicine in this country. Unless there’s substance behind these recommendations, including policy changes and reimbursement changes, it’s really not as effective as it could be.” FitzGerald agrees, noting that while many promising strategies and research pathways exist, there’s precious little in the way of allocated budget to support this.”

Tilo Grosser, MD, and Garret FitzGerald, MD, have called for a major, multifaceted scientific initiative to better treat pain as part of the complex solution to the opioid crisis.

The Mirror Crisis: Chronic Pain

When acute traumatic or post-surgical pain becomes chronic, or when a patient is living with a chronic pain condition, the limited palette of available treatments becomes an even more critical issue. “The options that people have for chronic pain really are minimal and quite pathetic,” says Garret FitzGerald. “Our approach to developing novel analgesics is like something out of the 19th century.”

For the 100 million adults in the U.S. with chronic pain, that leaves a major unmet need. “We may have an opioid ‘epidemic,’ but we also have a pain epidemic,” Martin Cheatle says. He points out that the annual cost of pain is 560 to 600 billion dollars, a huge sum in comparison to major diseases including heart disease and cancer.

Most of Cheatle’s patients suffer with nonmalignant chronic pain. “They’re the ones that have had layers and layers and layers of traumas, both physical and emotional,” he says. “Pain patients in general feel fairly vilified, they don’t feel that they’re taken seriously, they don’t feel that health care providers really listen to them, and I think there’s pretty persuasive evidence that when pain goes from no pain to acute to chronic, it becomes a brain disease. It’s not a symptom or a psychiatric disorder.”

The result is a neglected flip side to the current crisis. Despite the clear dangers of opioid abuse, there are many chronic pain patients who need the medications and can handle them just fine. Some patients who are safely taking fairly low doses of opioids are seeing their prescriptions taken away because of widespread concern about abuse, Cheatle says. And new prescriptions are harder to obtain, even for those for whom opioids may be a part of the best treatment plan. “Now the pendulum has swung to the other side.”

That can drive chronic pain patients to desperate and dangerous measures, such as turning to illicit alternatives when legitimate treatment is cut off. Kit Delgado recalls what he calls “a very common scenario”: a back surgery patient from out of town who continued to have post-surgical pain. After her opioid prescription was discontinued and she was unable to wait four months for an appointment to a pain medicine clinic, she ultimately turned to heroin for pain control. “I agree that we need to be more careful stewards of opioids, especially for acute prescribing, but now we have this huge population of people who are dependent on these, and what we’re seeing is the unintended consequences of acutely limiting prescriptions to these people and making it harder to get them,” he says. “And because heroin is a lot cheaper than prescription opioids, people are unfortunately swapping one for the other, and we’re seeing the devastating public health consequences right now.”

Getting Down To Business

The magnitude of the present crisis and the state of pain medicine led FitzGerald, along with Grosser and Clifford J. Woolf, to call for a major and multifaceted scientific initiative to identify better pain treatments in a Science article in March. Such a goal was also set out in a new report on the opioid crisis by a National Academies of Sciences committee, on which FitzGerald served.

FitzGerald compares the situation to AIDS in the 1980s, pointing out that more people now die every day of opioid abuse than died at AIDS at the peak of that crisis. More than a number, successfully confronting AIDS has required addressing a confluence of political, social, scientific, and criminal dimensions. FitzGerald contends that a similar broad-based campaign is critical for opioids. “What we don’t have is a coordinated, strategic, well-financed initiative that reflects the importance of this crisis and the depth of investment that it demands.”

In the Science article, the team suggests the establishment of a $10 billion research fund administered by the National Institutes of Health to pursue intensive research into the neurobiology of pain, the development of new drugs, and studying pain phenotypes (i.e., the varying responses of different individuals to medication). That amount is small in comparison to the expense of fighting AIDS, FitzGerald notes, but even the higher expenditures on AIDS ultimately cost far less than letting that crisis worsen with a less coordinated intervention. “And $10 billion would be a very cost effective investment if it got on top of this crisis.”

FitzGerald finds plenty of agreement for the notion that the solution to the opioid crisis is not going to come solely from the trenches, the doctors seeing patients every day or treating overdoses in emergency rooms. “We need a top-down reformation and legislators, insurance companies, the pharmaceutical industry have to put their money where their mouth is,” says Cheatle. “And until we do that, people are going to continue to suffer both from unremitting pain and from substance use disorders.” FitzGerald also emphasizes the responsibility of the pharmaceutical industry, especially given its role in creating the crisis. “They have a real societal and moral obligation to invest in a solution, and that needs to be spelled out, I think.”

That might sound like an uncomfortably political stance for doctors and scientists to take. But FitzGerald and his colleagues, working to achieve a better understanding of pain to help patients while averting the dangers of opioids, are unapologetic. “It is political. It should be political,” says FitzGerald. “But the solution should be a completely ideologically independent one, because it’s a bipartisan problem and it demands a bipartisan solution,” he insists.

“It needs to be a national priority.” 

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This article has been updated to correct a statistic about the U.S. use of the world’s opioid supply. The country uses about 50 percent, not 80 percent of these drugs. Source: International Narcotics Control Board of the World Health Organization.

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