The drug industrys answer to opioid

addiction: More pills

UNNATURAL CAUSES: SICK AND DYING IN SMALL-TOWN AMERICA |
Since the turn of this century, death rates have risen for whites in
midlife, particularly women. In this series, The Washington Post is
exploring this trend and the forces driving it.

By Ariana Eunjung Cha October 16 at 7:31 AM

Cancer patients taking high doses of opioid painkillers are often

afflicted by a new discomfort: constipation. Researcher Jonathan

Moss thought he could help, but no drug company was interested

in his ideas for relieving suffering among the dying.
So Moss and his colleagues pieced together small grants and, in
1997, received permission to test their treatment. But not on
cancer patients. Federal regulators urged them to use a less frail
and by then, rapidly expanding group: addicts caught in the
throes of a nationwide opioid epidemic.
Suddenly, Moss said, investors were knocking at his door.
As clinicians, we wanted to help palliative patients, said Moss, a
professor and physician at University of Chicago Medicine. The
company that bought our work saw a broader market.
Today, Mosss side project is hailed as the next billion-dollar drug.
And the once-disinterested pharmaceutical industry is
bombarding doctors and the public with information about a
serious, if previously unrecognized, condition common among the
millions of Americans who take prescription painkillers. They call it
opioid-induced constipation, or OIC.
The story of OIC illuminates the opportunism of pharmaceutical
innovators and the consequences of a heavily drug-dependent
society. Six in 10 American adults take prescription drugs,
creating a vast market for new meds to treat the side effects of
the old ones.
[In a town where pills are currency, opioid addicts have few
options]

Opioid prescriptions alone have skyrocketed from 112 million in

1992 to nearly 249 million in 2015, the latest year for which
numbers are available, and Americas dependence on the drugs
has reached crisis levels. Millions are addicted to or abusing
prescription painkillers such as OxyContin, Vicodin and Percocet.
Statistics from the Centers for Disease Control and Prevention
show that, from 1999 to 2014, more than 165,000 people died in
the United States from prescription-opioid overdoses, which have
contributed to a startling increase in early mortality among
whites, particularly women a devastating toll that has hit
hardest in small towns and rural areas.
The pharmaceutical industrys response has been more drugs.
The opioid market now worth nearly $10 billion a year in sales
in the United States has expanded to include a growing
universe of medications aimed at treating secondary effects
rather than controlling pain.
Theres Suboxone, financed and promoted by the U.S.
government as a safer alternative to methadone for those trying
to break their dependence on opioids. Theres naloxone, the
emergency injection and nasal spray carried by first responders to
treat overdoses. And now theres Relistor, the drug based on
Mosss work, and a competitor, Movantik, for constipation.
In colorful charts designed to entice investors, numerous
pharmaceutical makers tout the expansion opportunity that
exists in the opioid use disorders population.
Indivior, a specialty pharmaceutical company listed on the London
Stock Exchange, sees around 2.5m potential patients, the
majority of whom are addicted to prescription painkillers, as
opposed to illicit drugs such as heroin. Another company, New

Jersey-based Braeburn Pharmaceuticals, highlights growth

drivers for the market, noting that millions of additional
Americans not yet identified are also likely to be dependent on
opioid painkillers.
Analysts estimate that each of these submarkets addiction,
overdose and side effects is worth at least $1 billion a year in
sales. These economics, experts say, work against efforts to end
the epidemic.
If opioid addiction disappeared tomorrow, it would wipe billions of
dollars from the drug companies bottom lines.

A potent product
From a profit-making standpoint, opioids are a potent product.
Chronic use can cause myriad side effects that usually are mild

enough to keep people taking painkillers but sufficiently

uncomfortable to send them back to the doctor.
Andrew Kolodny, executive director of Physicians for Responsible
Opioid Prescribing, said this domino effect can turn a patient
worth a few hundred dollars a month into one worth several
thousand dollars a month.
Many patients wind up very sedated from opioids, and its not
uncommon to give them amphetamines to make them more alert.
But now they cant sleep, so they get Ambien or Lunesta. The
amphetamines also make them anxious, paranoid and sweaty,
and that means even more drugs, said Kolodny, who also serves
as chief medical officer to Phoenix House, a nonprofit organization
that offers drug and alcohol treatment in 10 states and the
District.
Women, in particular, are ideal customers. About 57 percent of
working-age women who take opioids have four or more
prescriptions, according to a Washington Post analysis of
participants in the latest National Health and Nutrition
Examination Survey. Among working-age women who dont take
opioids, 14 percent have four or more prescriptions, the analysis
shows.
Among men, the numbers are significantly lower. About 41
percent of working-age men on prescription opioids have at least
four prescriptions. Among men who dont take opioids, 9 percent
have four or more.
[Opiods and anti-anxiety medication are killing white American
women]

Studies show that constipation afflicts 40 percent to 90 percent of

opioid patients. As recently as a few years ago, doctors typically
advised people to cut down the dosages of their pain meds, to
take them less often, or to try non-drug interventions such as
changing their diets or increasing physical activity.
By promoting opioid-induced constipation as a condition in need
of more targeted treatment, critics say the drug industry is
creating incentives to maintain the painkillers at full strength and
add another pill instead.
The pharmaceutical industry literally created the problem [of
OIC], Kolodny said. They named it, and they started advertising
what a serious issue it is. And now theyve got the solution for it.

A Super Bowl ad
Opioid-induced constipation burst onto the biggest possible public
stage in February, when AstraZeneca, maker of Movantik, aired a
spot during Super Bowl 50 , one of the most expensive ad
opportunities of the year. It featured a middle-aged man wistfully
watching another man triumphantly adjusting his belt, a dog
peacefully relieving itself under a tree and a woman striding by
with a banner of toilet paper trailing victoriously from one highheeled shoe.
If you need an opioid to manage your chronic pain, you may be
so constipated it feels like everyone can go except you, a
narrator intones.
That ad was aimed at men, but many others in the Movantik
campaign target women, airing on Good Morning America,
movies on the Hallmark Channel and specials about former first
lady Jacqueline Kennedy, Princess Diana and singer Whitney
Houston.
In one, a slightly overweight dark-blonde woman talks about
struggling to find relief. In another, a giant cartoon pill looms
sympathetically over a middle-aged brunette, who complains that
opioids really helped with her pain but left her with some
baggage.
So awkward, she sighs.
The Super Bowl ad, aired before an audience of more than 100
million people, quickly became the latest flash point in the

countrys war against opioids. Vermont Gov. Peter Shumlin (D)

called the ad a shameful attempt to exploit Americas addiction
crisis to boost corporate profits. White House chief of staff Denis
McDonough tweeted: Next year, how about fewer ads that fuel
opioid addiction and more on access to treatment.
AstraZeneca and its marketing partner Daiichi Sankyo defended
the commercials, calling opioid-induced constipation a legitimate
medical condition affecting millions of Americans.
The ad has driven good dialogue about OIC, and just as
importantly, also added to the increasing and necessary
conversation about the appropriate and safe use of opioids, a
spokeswoman said.
Paul Gileno, president of the U.S. Pain Foundation, a patient
advocacy group that worked with AstraZeneca on the ads, notes
that many people use opioids responsibly.
People ask, Why are you helping addicts? Thats not the case,
Gileno said. We are trying to help people who are suffering from
chronic pain to be able to continue on their medicines and live
their lives.

A brilliant pitch
Each tiny pink pill of Movantik retails for about $10, and most
insurance plans cover it. Since the Super Bowl, prescriptions have
jumped from 6,600 to 8,800 a week, AstraZeneca recently
reported.

Movantik holds the dominant market share, but Canadas Valeant

Pharmaceuticals one of the companies under fire by Congress
for jacking up prices of old drugs won approval in July from the
Food and Drug Administration to sell Relistor, its version of the
pill. Analysts estimate that as many as six other drugs may be on
the market by 2019.
Investors have been talking about the blockbuster potential of
these drugs since at least 2008, when Movantik had been tested
on only a small number of human subjects, and long before it
received FDA approval in 2014. While it is illegal to market a drug
before approval, it is fine to market the condition the drug is
designed to treat. And so OIC was born.
The branding began around 2010, when OIC began appearing in
papers in some of the top medical journals, in poster
presentations and on the lips of panelists speaking at major
medical conferences. Opioid-induced constipation suddenly
replaced what had been a vast vocabulary used to describe the
problem, including terms such as bowel dysfunction and gut
motility.
Last year, after it won government approval to sell Movantik,
AstraZeneca rolled out a number of free continuing-education
classes. Doctors and nurses must take such classes to remain
licensed. The titles included: Opioid-induced Constipation: A
Neglected Complication and Unmet Needs in Opioid-Induced
Constipation.
The companies have also asked pain doctors to show patients a
chart about stool health, with diagrams to help assess shape
and clumpiness.

Adriane Fugh-Berman, a researcher at Georgetown University

Medical Center who studies drug marketing, called the Movantik
strategy brilliant. She compared it to other recent disease
awareness campaigns focused on premenstrual dysphoric
disorder (treatable with a new version of Prozac packaged in pink
instead of blue) and binge-eating disorder (for which there is a
new pill called Vyvanse).
The OIC campaign created the perception of great need for the
drug when the market should be vanishingly small, FughBerman said certainly not big enough to justify ads during the
Super Bowl.

The best way to treat opioid-induced constipation, she said, is

to prevent it in the first place by not overusing opioids.

Moss reluctantly continued to test a constipation-easing drug he

was developing on opioid addicts, rather than cancer patients, at
the behest of the Food and Drug Administration. It became
Valeants Relistor. (Lucy Hewett)

William Chey, director of the Gastrointestinal Physiology

Laboratory at the University of Michigan, helped design and
execute the first large-scale human study for a competing drug
that became Movantik, the first drug on the market specifically
approved to treat opioid-induced constipation. (Nick Hagen)
Potential for good and bad
Constipation is different for people on opioids. Opioids bind to a
receptor that makes the gastrointestinal tract go awry, decreasing
the secretion of fluids and inhibiting the muscle contractions that
propel waste. As a result, stool gets stuck.

While mostly a nuisance, the condition can be serious, especially

among people already weakened by end-stage cancer. Some
patients have been rushed to the emergency room to have the
material removed from their bodies.
In the early 1990s, Moss and his colleagues at the University of
Chicago began working on a drug that would block what are
known as mu opioid receptors, which are responsible for the side
effect. The drug showed promise, and Moss was devastated when
investors told him the potential profits were too small to be worth
the risky investment.
If youre a drug company, who wants to make a drug for people
who werent going to be around in a couple of months? They
wanted to aim for something people could take for 10, 20 years,
recalled Moss, who specializes in anesthesiology and critical care.
The researchers decided to fund the work without industry help
but ran into another roadblock: The FDA said it was too risky to
continue testing the experimental drug on cancer patients.
Regulators suggested a different population: opioid addicts being
treated with methadone.
Moss was reluctant. He considered the idea a detour that would
slow down his work. Our hearts really sank, he said.
Thinking that he had no choice, Moss began the testing, and the
results were published in JAMA, the Journal of the American
Medical Association, in 2000. Pharmaceutical companies
immediately came calling.

Mosss drug was picked up by a biotech company and, after

changing hands a few times, eventually became Valeants
Relistor. Nearly all the profits will go to the companies. The
licensing deal through the University of Chicago calls for Moss and
four colleagues to receive a modest initial payment in the
thousands of dollars, plus a tiny slice of sales royalties. They also
get milestone payments when the drug reaches a certain stage
of approval or a certain market size.
Parallel efforts took off at other companies. Nektar Therapeutics,
a small San Francisco firm specializing in drug research and
development, had been working on a drug known as NKTR-118,
which was aimed at limiting opioid penetration of the central
nervous system and reducing side effects such as dizziness and
sleepiness. But researchers found that it also helped with
constipation.
In 2009, AstraZeneca bought the rights for the drug and recruited
William Chey, director of the Gastrointestinal Physiology
Laboratory at the University of Michigan, to help design and
execute the first large-scale human study. The results, published
in the New England Journal of Medicine in 2014, were a crucial
part of pushing Movantik over the FDA finish line. Last year, it
became the first drug on the market specifically approved to treat
opioid-induced constipation.
Chey said that he has seen many patients with cancer and other
serious illnesses suffering from the condition and that he believes
Movantik can improve their quality of life. However, Chey said he
also recognizes the concern that Movantik could enable chronic
opioid use and worsen the nations epidemic of addiction.

Ive thought a lot about the potential good and bad, he said.
Used responsibly, this is an incredibly valuable drug. Hopefully,
people will use it that way.
Dan Keating contributed to this report.
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