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, Moss’s 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.

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 America’s 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 industry’s 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.

There’s Suboxone, financed and promoted by the U.S. government as a safer alternative to methadone for those trying to break their dependence on opioids. There’s naloxone, the emergency injection and nasal spray carried by first responders to treat overdoses. And now there’s Relistor, the drug based on Moss’s 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.

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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 it’s not uncommon to give them amphetamines to make them more alert. But now they can’t 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 of Columbia.

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 don’t 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 don’t take opioids, 9 percent have four or more.

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 they’ve got the solution for it.”

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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 high-heeled 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 country’s war against opioids. Vermont Gov. Peter Shumlin (D) called the ad “a shameful attempt to exploit America’s 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?’ That’s 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.”

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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 Canada’s 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 few dozen 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,” Fugh-Berman 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.”

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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 you’re a drug company, who wants to make a drug for people who weren’t 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.

Moss’s drug was picked up by a biotech company and, after changing hands a few times, eventually became Valeant’s 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 of several thousand 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, Astra Zeneca 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 nation’s epidemic of addiction.

“I’ve 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.”