To prescribe or not prescribe? In the realm of the nation’s opioid epidemic, it’s an important question.

Research has shown that inappropriate use of prescription opioids is part of the reason behind a dramatic rise in opioid-related deaths since 2000. By 2015, the amount of opioids prescribed in the U.S. had tripled — enough for every American to be medicated around the clock for three weeks, at 5 milligrams of hydrocodone every four hours. 

Now, new research by a trio of Stanford scholars shows how different insurance strategies affect the volume of opioid use and could help stem inappropriate prescribing behaviors. 

The study, released in a working paper by the National Bureau of Economic Research, was co-authored by Stanford Health Policy’s Laurence C. Baker, M. Kate Bundorf, and Daniel P. Kessler. Baker and Bundorf are professors in the Department of Health Research and Policy at the Medical School; Kessler is a professor in the Law School and Graduate School of Business, and a senior fellow at the Hoover Institution.  All are also senior fellows at the Stanford Institute for Economic Policy Research (SIEPR).

Their study — the first to investigate the effect of the form of Medicare drug coverage on opioid use — found that enrollment in Medicare Advantage, a combined medical and drug insurance plan, significantly reduces the likelihood of beneficiaries filling an opioid prescription, as compared to enrollment in a stand-alone drug plan.

Compared to beneficiaries enrolled in stand-alone plans, those enrolled in the integrated Medicare Advantage plan were 37 percent less likely to get an opioid prescription, according to their analysis of drug claims from 2014.

The researchers also found that enrollment in integrated insurance coverage under Medicare Advantage had a disproportionate effect on the likelihood of filling an opioid prescription from the nation’s highest opioid-prescribing doctors — the top 1 percent of prescribers in Medicare Part D. The lower likelihood of prescriptions from these high prescribers to Medicare Advantage enrollees accounted for more than half of the reduction, according to their findings.

To understand the scope of this health plan-related effect and what’s at stake, consider the backdrop laid out in the study:

Since its implementation in 2006, Medicare Part D has become the nation’s largest purchaser of prescription opioids. More than 42 million Americans are enrolled in Medicare Part D — either under the stand-alone drug plan or the integrated Medicare Advantage plan.

What’s more, opioid prescriptions are concentrated among a relatively small group of “high prescribers.” 

According to research published in the 2016 edition of JAMA Internal Medicine, more than one-third of opioid prescriptions under Medicare Part D were made by about 8,000 doctors, making up the top 1 percent of prescribers. And according to the Office of the Inspector General of the Department of Health and Human Services, “extreme use” and “questionable prescribing” have put almost 90,000 beneficiaries at serious risk for opioid misuse or overdose.

Because the researchers did not examine patient health outcomes, they could not definitively determine that enrollment in Medicare Advantage reduced only inappropriate opioid use. However, because the reduction in opioid use came disproportionately from high prescribers, and previous work has found that Medicare Advantage enrollees had higher prescription drug use overall, the reduction in use that the researchers found was targeted rather than a result of a broader effort to restrict access to treatment.  

The researchers’ results support the conclusions of previous work that integration of prescription drug coverage with the other benefits provided by Medicare Advantage plans

improves the quality of care. Further study will be needed to drill deeper into the reasons behind the impact of Medicare Advantage plans, and whether a similar effect occurs in non-elderly populations, the researchers said.

The national opioid epidemic has grown at such breakneck speed that public health experts have been left scrambling to keep up. Though they understand the reasons behind the abuse — the solutions are complicated and costly.

Yet there appears to be some success at reducing at least one area of opioid abuse.

In new research by Health Research and Policy’s Eric Sun, the risk for chronic opioid use among patients with musculoskeletal pain actually decreased slightly between 2008 and 2014. 

The Stanford Medicine assistant professor of anesthesiology and pain medicine found that measures such as avoiding opioid use soon after diagnosis can further reduce the risk of addiction, especially among patients at highest risk for chronic opioid use.

"We found that early opioid use after diagnosis is predictive of opioid use longer term, suggesting that it may be prudent to minimize opioid use where possible for patients with musculoskeletal pain,” said Sun, whose research was published earlier this week in the Annals of Internal Medicine.

His co-authors are Jasmin Moshfegh, who is working on her PhD in health policy, and Steven Z. George, director of musculoskeletal research at Duke University School of Medicine.

Patients with lower back or chronic neck, shoulder and knee pain are at the highest risk for opioid abuse since pain meds are typically prescribed to help ease their spasms. 

Patients who suffer musculoskeletal pain may unwittingly transition to chronic opioid use, which means filling 10 or more prescriptions or having a supply for at least 120 days. The prescription drugs include hydrocodone, hydromorphone, methadone, morphine, oxymorphone, and/or oxycodone. Those don’t include heroin and synthetic opioids such as fentanyl.

Sun and his fellow researchers at the Stanford University School of Medicine used a large health-care database to assess the risk and risk factors for chronic opioid use among more than 400,000 “opioid-naïve” patients — those who have never been prescribed painkillers before — recently diagnosed with pain in the knee, neck, lower back or shoulder. 

The sample was restricted to privately insured patients, thereby excluding other policy-relevant populations, such as those who were prescribed pain medications under Medicare or Medicaid.

They found that risk for chronic opioid use ranged from 0.3 percent for knee pain to 1.5 percent for multiple-site pan and decreased for some anatomical regions during the timeframe studied. They discovered a relative decline of 25 to 50 percent across all pain types from 2008 to 2014.

Opioid Abuse

Opioid abuse has its roots in the late 1990s when pharmaceutical companies assured the medical community that patients would not become addicted to pain relievers. Clinicians began prescribing them at greater rates because they worked so well and seemed safe.

Today, more than 130 people die every day from opioid-related drug overdoses from prescription pain relievers, heroin and synthetic opioids such as fentanyl, according to the U.S. Department of Health and Human Services, From 2002 to 2017, there was more than a fourfold increase in opioid deaths, with some 49,000 people dying in 2017.

The Centers for Disease Control and Prevention estimates that the total economic burden of prescription opioid misuse alone in the United States is $78.5 billion a year, including the costs of health care, lost productivity, addiction treatment and criminal justice involvement.

“While our research found that only about 1 percent of patients with musculoskeletal pain progress to chronic opioid use, this is potentially concerning because it’s an extremely common diagnosis,” Sun said. “By pointing out the scope of the issue and identifying factors that place patients at risk, we hope this research will guide further efforts aimed at reducing opioid use among patients with musculoskeletal pain.” 

People who are acquainted with the work of Shorenstein APARC’s Asia Health Policy Program (AHPP) may be aware of the Innovation for Healthy Aging collaborative research project led by APARC Deputy Director and AHPP Director Karen Eggleston. This project, which identifies and analyzes productive public-private partnerships advancing healthy aging solutions in East Asia and other regions, encompasses an upcoming volume, co-authored by Eggleston with Harvard University professors Richard Zeckhauser and John Donohue, about public and private roles in governance of multiple sectors in China and the United States, including health care and elderly care. This volume, however, is not the first collaboration between Eggleston and Zeckhauser.

Zeckhauser, the Frank P. Ramsey Professor of Political Economy at Harvard University’s Kennedy School, is known for his many policy investigations that explore ways to promote the health of human beings, to help markets work more effectively, and to foster informed and appropriate choices by individuals and government agencies. In 2006, Eggleston and Zeckhauser co-wrote a paper about antibiotic resistance as a global threat, an issue that has since received much attention as it has become a critical public health and public policy challenge. Zeckhauser was a pioneer in framing antibiotic resistance as a global threat.

On October 20, 2018, Eggleston was among some 150 colleagues, students, and friends who participated in a special symposium at the Kennedy School to celebrate Zeckhauser’s 50th anniversary of teaching and research, and to anticipate what the next 50 years might bring in the multiple fields he has influenced throughout his long career.

Eggleston joined the first of two panels in that symposium, where she spoke about Zeckhauser’s impact on health policy and about what academics and policymakers should be tackling next on the path to addressing the global threat of antibiotic resistance.

The panel was moderated by Harvard Professor Edward Glaeser. In addition to Eggleston, it included Jeffrey Liebman, Daniel Schrag, and Cass Sunstein.

A video recording of the panel is made available by the Kennedy School. Listen to Eggleston’s remarks (beginning at the 8:42 and 36:20 time marks):

Preeclampsia is a serious complication of pregnancy that affects 5 to 10 percent of all pregnancies — over 8 million a year worldwide — and claims the lives of 76,000 mothers and half a million babies each year.

The condition causes hypertension and abnormal protein in the urine, and has few effective preventive or therapeutic strategies. The clinical abnormalities usually resolve completely after delivery, but recent research shows that women who have had preeclampsia have higher rates of heart disease later in life, for reasons that are poorly understood.

That’s where Mark Hlatky, Virginia Winn, and their Stanford Medicine research team come in. They were recently awarded a 4-year, $6 million NIH grant from the National Heart, Lung and Blood Institute to study the links between preeclampsia and the subsequent risk of atherosclerotic cardiovascular disease (ASCVD) as women grow older.

“The goal of this study is to improve cardiovascular health in women, by learning how pregnancy affects heart disease later in life,” said Hlatky, a Stanford Health Policy fellow. “We hope that shedding new light on these links can lead to better prevention and treatment.”

The interdisciplinary study called EPOCH — Effect of Preeclampsia On Cardiovascular Health — could eventually help millions of women and their clinicians worldwide.

“Since about 85 percent of women become pregnant at some point during their lives, and heart disease is the leading cause of death in women, determining how pregnancy complications might increase the risk of heart disease later in life could be very important,” said Hlatky, a professor of health research and policy and of cardiovascular medicine. “If there is a specific biomarker ‘signature’ of heart disease risk in women who have had preeclampsia, it would open up new possibilities for risk assessment and better treatment to prevent heart attacks and strokes.”

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Hlatky and his co-principal investigator, Stanford high-risk obstetrician Winn, note that a history of preeclampsia doubles the woman’s risk of future heart disease and stroke, and triples her risk of hypertension. And these adverse consequences occur at younger ages than in women who never developed the condition during pregnancy.

"The dramatic physiologic changes that happen during pregnancy are indeed remarkable," said Winn, the Arline and Pete Harman faculty scholar in the Department of Obstetrics and Gynecology. "This study highlights how complications that occur in pregnancy impact women's health beyond pregnancy." 

The pathogenic links between preeclampsia early in life and ASCVD late in life have been difficult to investigate because the process develops over decades, the authors said. And few clinicians are aware of the link between the condition and late ASCVD risk and there are no validated biomarkers for this process.

Preliminary data that contributed to the application of the project was a direct result of Winn’s endowed Arline and Pete Harman Faculty Scholar award and funding from the Stanford Maternal and Child Health Research Institute and the Stanford Cardiovascular Institute.

The 4-year grant will support a multi-disciplinary research team in taking a life-course approach. The EPOCH study will enroll three cohorts of women at distinct points in the natural history of the disorder: during pregnancy in their reproductive years; during the long, asymptomatic period in mid-life; and the ultimate development of ASCVD in later life.

“It’s very difficult to study the effects of early life events on the development of diseases late in life, since they are separated by 40 years or more,” Hlatky said. “We don’t have reliable health records in the United States from 40 or more years ago, so it’s a challenge for American researchers.” This is why, he said, the EPOCH study includes researchers from Denmark, which has a national health system, complete medical data of their citizens since the 1970’s, and a national biobank that will allow study of later life events.

The first cohort of women will include some of those who are already part of the Stanford March of Dimes Prematurity Research Center. The center, led by David Stevenson began recruiting women in 2011 to study pregnancy from the first trimester through delivery. The study has collected a wide array of “omics” measures at multiple time points: metabolomics, proteomics, cell-free RNA, the microbiome and immune cells for analysis, as well as collection of amniotic fluid, cord blood, and the placenta. The pregnancy cohort will enroll additional women who are cared for at Lucile Packard Children’s Hospital for treatment of preeclampsia, about 100 in all, plus a matched group with uncomplicated pregnancies.

This is where it gets pretty technical — but also pretty cool

The researchers will collect high-dimensional “omic” biomarker data to assess the pathophysiology of preeclampsia and its relationship to cardiovascular function and disease. They’ll assess cell signaling pathways using single-cell immune profiling (CyTOF) methods in the lab of Brice Gaudilliere, an assistant professor of anesthesia.

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They will then analyze the cell-free RNA profiles using methods developed by co-investigator Stephen Quake, a professor of bioengineering and applied physics, and co-president of the Chan Zuckerberg Biohub. They will assess metabolomics using novel methods also developed at Stanford by co-investigator Michael Snyder,  professor and chair of genetics.

Stanford data scientists, including co-investigators, Robert Tibshirani and Nima Aghaeepour, have been at the forefront of developing and applying novel statistical and bioinformatic approaches, which the team will use to analyze the torrents of data that can now be collected by modern “omics” technologies from individual clinical research subjects.

“The EPOCH study is truly interdisciplinary — we are bringing together faculty from eight different departments to study a major problem in women’s health.”

The second, mid-life cohort will be recruited from women who had a pregnancy complicated by preeclampsia. Marcia Stefanick, professor of medicine in the Stanford Prevention Research Center, will use the Stanford Medicine Research Data Repository (STARR), which contains electronic records from more than 1.6 million patients since 1995, to identify eligible women. Stefanick and the EPOCH team will recruit 200 pre-menopausal women who had either a pregnancy complicated by preeclampsia or an uncomplicated pregnancy.

The third, late-life cohort of women will be identified in the Danish National Biobank by Stanford visiting professor Mads Melbye. Samples will be retrieved from women who had preeclampsia early in life and ASCD later in life, as well as a set of matched control subjects, and analyzed in Stanford laboratories.

“We’re not quite sure whether the physiologic challenges of pregnancy that result in preeclampsia simply reveal underlying cardiovascular risk, or causes change that leads to the increased risk in later life,” Winn said. “The EPOCH study will identify unique aspects of preeclampsia that links it to later ASCVD, opening potential novel approaches to improve women’s health.”

The EPOCH study brings together investigators from eight departments. Additional faculty include Gary Shaw and Seda Tierney (Pediatrics), Martin Angst (Anesthesia), Nicholas Leeper (Surgery) and Heather Boyd (Danish Biobank).

In Beijing’s bustling Chaoyang District stands a multi-story building known as the Gonghe Senior Apartments: a 400-bed nursing home for middle-income seniors who are disabled or suffer from dementia. Why is Gonghe unique and why is it worth considering? Because Gonghe is a public-private partnership (PPP), a collaborative organizational structure supported by the District Civil Affairs Bureau Welfare Division that donated the land and building and the nonprofit Yuecheng Senior Living that operates the facility. And because PPPs like Gonghe might just be the right model to address the challenges surrounding elderly care in China as well as in other nations that face a looming burden of population aging.

This was a core message shared by Alan Trager, founder and president of the PPP Initiative Ltd., who spoke at a special workshop organized by Shorenstein APARC’s Asia Health Policy Program (AHPP). Focused on PPPs in health and long-term care in China, the workshop was part of a two-day convening related to the Innovation for Healthy Aging project, a collaborative research project led by APARC Deputy Director and AHPP Director Karen Eggleston that identifies and analyzes productive public-private partnerships advancing healthy aging solutions in East Asia and other regions.

The Innovation for Healthy Aging project is driven by the imperative to respond to a world that is aging rapidly. This demographic transition, reminded Trager at the opening of his talk, is a defining issue of our time, as aging is a multisectoral issue that increases the demand for health care, long-term care, and a large number of other social services. The aging challenge is exacerbated by its convergence with the rising prevalence of non-communicable diseases (NCDs), also known as chronic diseases. For while NCDs affect all age groups, they account for the highest burden among the elderly.

China: Ground Zero for Global Aging

Alan Trager discusses health and long-term care in China in the GSB's Highly Immersive Classroom

The need to advance healthy aging and NCD prevention is a matter of grave concern in China, whose older population is larger than in any other country. Moreover, the aging challenge in China is interwoven with unique social trends. In particular, filial piety—which, for thousands of years, has been a fundamental family value and a mainstay of health and elder care—is under pressure, as young people strive to balance the demands of careers, fewer children per family, and migrating to cities for school and work, without affordable housing or long-term care financing support for their parents and other elderly relatives, who often stay in rural areas.

China’s health system is yet to adapt to the shift in the disease burden and health care needs driven by the aging population. Its existing health insurance programs are insufficient for outpatient management and care of chronic conditions, and as Trager emphasized, there is a lack of investment in training geriatric medicine professionals and incorporating geriatric principles into clinical practice.

How can China meet the high demand for elder care, increase workforce capacity, and promote healthy aging?

The answer, claims Trager, lies in developing multisector, integrated solutions to the challenges posed by population aging. While system-level efforts, such as building the social protection system and sustaining universal health coverage, continue to be led by the government, PPPs can play a major role in capacity building to ensure the sustainability of such systems through the advancement of technology, human resources, and innovation. Trager shared PPP Initiative Ltd.’s recent efforts to develop PPP solutions for aging populations in China and elsewhere. The workshop was held on October 10 at the Stanford GSB’s Highly Immersive Classroom, which is equipped with advanced video conferencing technology that allows participants in Palo Alto and at the Stanford Center at Peking University to collaborate in real-time. Experts from Beijing joined the discussion and followed Trager’s presentation with comments on how to move from awareness to action.

Private Efforts, Public Value

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Public-private collaborations—or rather collaborative governance–in China as well as in the United States is the subject of an upcoming volume co-authored by Eggleston with Harvard scholars Richard Zeckhauser and John Donahue. Both Zeckhauser and Donahue joined Eggleston the following day, October 11, at an AHPP-hosted seminar to discuss this upcoming publication, titled Private Roles for Public Goals in China and the United States: Contracting, Collaboration, and Delegation.

Eggleston, Donahue, and Zeckhauser define collaborative governance as private engagement in public tasks on terms of shared discretion, where each partner bears responsibilities for certain areas. Their upcoming book explores public-private collaborations in China and the United States, two countries where public needs require solutions that far outstrip the capacities of their governments alone. Beyond considering merely health and elderly care, the book features research into public and private roles in the governance of multiple other sectors, including education, transport infrastructure, affordable housing, social services, and civil society.

At the seminar, the three scholars reviewed different models of private efforts providing public value, outlined the justifications for collaborative governance, and explained some of the conditions that make such collaborative partnerships productive and valuable. They emphasized the need to account for the unique contexts in China and the United States and to steer clear of one-size-fits-all solutions.

Imperative for the Young Generation

One thing, they all agree, applies to both countries: government collaboration with private entities is inevitable if China and the United States are to achieve their articulated goals and meet rapidly increasing demand for high-end public services.

This sentiment echoed a claim Trager made the preceding day: a tidal wave of noncommunicable diseases in an aging world is approaching us quickly and governments cannot handle it alone. Young people must care about advancing creative solutions to this pressing problem because they will be the ones who will pay for the consequences if we get it wrong.

In this recent lecture at Cornell University’s Contemporary China Initiative, Karen Eggleston, Shorenstein APARC deputy director and the Asia Health Policy Program director, talks about China’s health system reforms, including progress to date in achieving effective universal coverage, priorities set in the national health meetings, Healthy China 2030 goals, and local experiments in strengthening patient-centered integrated care.

CCCI October 1, 2018: Karen Eggelston from Cornell East Asia Program.

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